Compounds for the treatment of hepatitis C

ABSTRACT

The invention encompasses compounds of formula I as well as compositions and methods of using the compounds. The compounds have activity against hepatitis C virus (HCV) and are useful in treating those infected with HCV.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 61/049,944 filed May 2, 2008 and 60/954,814 filed Aug. 9, 2007.

BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) is a major human pathogen, infecting anestimated 170 million persons worldwide—roughly five times the numberinfected by human immunodeficiency virus type 1. A substantial fractionof these HCV infected individuals develop serious progressive liverdisease, including cirrhosis and hepatocellular carcinoma (Lauer, G. M.;Walker, B. D. N. Engl. J. Med. 2001, 345, 41-52).

HCV is a positive-stranded RNA virus. Based on a comparison of thededuced amino acid sequence and the extensive similarity in the5′-untranslated region, HCV has been classified as a separate genus inthe Flaviviridae family. All members of the Flaviviridae family haveenveloped virions that contain a positive stranded RNA genome encodingall known virus-specific proteins via translation of a single,uninterrupted, open reading frame.

Considerable heterogeneity is found within the nucleotide and encodedamino acid sequence throughout the HCV genome. At least six majorgenotypes have been characterized, and more than 50 subtypes have beendescribed. The major genotypes of HCV differ in their distributionworldwide, and the clinical significance of the genetic heterogeneity ofHCV remains elusive despite numerous studies of the possible effect ofgenotypes on pathogenesis and therapy.

The single strand HCV RNA genome is approximately 9500 nucleotides inlength and has a single open reading frame (ORF) encoding a single largepolyprotein of about 3000 amino acids. In infected cells, thispolyprotein is cleaved at multiple sites by cellular and viral proteasesto produce the structural and non-structural (NS) proteins. In the caseof HCV, the generation of mature non-structural proteins (NS2, NS3,NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. Thefirst one is believed to be a metalloprotease and cleaves at the NS2-NS3junction; the second one is a serine protease contained within theN-terminal region of NS3 (also referred to as NS3 protease) and mediatesall the subsequent cleavages downstream of NS3, both in cis, at theNS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B,NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiplefunctions, acting as a cofactor for the NS3 protease and possiblyassisting in the membrane localization of NS3 and other viral replicasecomponents. The complex formation of the NS3 protein with NS4A seemsnecessary to the processing events, enhancing the proteolytic efficiencyat all of the sites. The NS3 protein also exhibits nucleosidetriphosphatase and RNA helicase activities. NS5B (also referred to asHCV polymerase) is a RNA-dependent RNA polymerase that is involved inthe replication of HCV. The HCV NS5B protein is described in “StructuralAnalysis of the Hepatitis C Virus RNA Polymerase in Complex withRibonucleotides (Bressanelli; S. et al., Journal of Virology 2002,3482-3492; and Defrancesco and Rice, Clinics in Liver Disease 2003, 7,211-242.

Currently, the most effective HCV therapy employs a combination ofalpha-interferon and ribavirin, leading to sustained efficacy in 40% ofpatients (Poynard, T. et al. Lancet 1998, 352, 1426-1432). Recentclinical results demonstrate that pegylated alpha-interferon is superiorto unmodified alpha-interferon as monotherapy (Zeuzem, S. et al. N.Engl. J. Med. 2000, 343, 1666-1672). However, even with experimentaltherapeutic regimens involving combinations of pegylatedalpha-interferon and ribavirin, a substantial fraction of patients donot have a sustained reduction in viral load. Thus, there is a clear andimportant need to develop effective therapeutics for treatment of HCVinfection.

DESCRIPTION OF THE INVENTION

One aspect of the invention is a compound of formula I

where:

R¹ is CO₂R⁵ or CONR⁶R⁷;

R² is furanyl, pyrrolyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl,imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, or tetrazolyl,and is substituted with 0-2 substituents selected from oxo, amino,alkylthio, alkyl, and haloalkyl, and 1 substituent selected from CO₂R⁵,CON(R¹²)₂, and COR¹³;

R³ is hydrogen, halo, alkyl, alkenyl, hydroxy, benzyloxy, or alkoxy;

R⁴ is cycloalkyl;

R⁵ is hydrogen or alkyl;

R⁶ is hydrogen, alkyl, alkylSO₂, cycloalkylSO₂, haloalkylSO₂,(R⁹)(R¹⁰)NSO₂, or (R¹¹)SO₂;

R⁷ is hydrogen or alkyl;

R⁸ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, alkylcarbonyl,cycloalkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, alkylSO₂,cycloalkylSO₂, haloalkylSO₂, aminocarbonyl, (alkylamino)carbonyl,(dialkylamino)carbonyl, benzyl, benzyloxycarbonyl, or pyridinyl;

R⁹ is hydrogen or alkyl;

R¹⁰ is hydrogen or alkyl;

R¹¹ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl,and is substituted with 0-1 alkyl substituents;

R¹² is hydrogen, alkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl,(dialkylamino)alkyl, or (R¹¹)alkyl;

R¹³ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl,and is substituted with 0-3 substituents selected from alkyl,alkoxyalkyl, amino, alkylamino, dialkylamino, R¹¹, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, (R¹¹)alkyl, or CO₂R⁵;

or R¹³ is

or R¹³ is

or R¹³ is a [4.3.0] or [3.3.0]bicyclic diamine attached to the carbonylthrough one nitrogen, and is substituted with 0-2 R⁸ substituents;

or R¹³ is

R¹⁴ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, or benzyl;

R¹⁵ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, or benzyl;

or NR¹⁴R¹⁵ taken together is azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, N-(alkyl)piperazinyl, morpholinyl, thiomorpholinyl,homopiperidinyl, or homomorpholinyl;

R¹⁶ is hydrogen or alkyl;

R¹⁷ is hydrogen, alkyl, or cycloalkyl; and

X is methylene, a bond, or absent;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where:

R¹ is CO₂R⁵ or CONR⁶R⁷;

R² is furanyl, pyrrolyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl,imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, or tetrazolyl,and is substituted with 0-2 substituents selected from oxo, amino,alkyl, and haloalkyl, and 1 substituent selected from CO₂R⁵, CON(R¹²)₂,and COR¹³;

R³ is hydrogen, halo, alkyl, alkenyl, hydroxy, benzyloxy, or alkoxy;

R⁴ is cycloalkyl;

R⁵ is hydrogen or alkyl;

R⁶ is hydrogen, alkyl, alkylSO₂, cycloalkylSO₂, haloalkylSO₂,(R⁹)(R¹⁰)NSO₂, or (R¹¹)SO₂;

R⁷ is hydrogen or alkyl;

R⁸ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, alkylcarbonyl,cycloalkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, alkylSO₂,cycloalkylSO₂, haloalkylSO₂, aminocarbonyl, (alkylamino)carbonyl,(dialkylamino)carbonyl, benzyl, benzyloxycarbonyl, or pyridinyl;

R⁹ is hydrogen or alkyl;

R¹⁰ is hydrogen or alkyl;

R¹¹ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl,and is substituted with 0-1 alkyl substituents;

R¹² is hydrogen, alkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl,(dialkylamino)alkyl, or (R¹¹)alkyl;

R¹³ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl,and is substituted with 0-3 substituents selected from alkyl,alkoxyalkyl, amino, alkylamino, dialkylamino, R¹¹, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, (R¹¹)alkyl, or CO₂R⁵;

or R¹³ is

or R¹³ is

or R¹³ is a [4.3.0] or [3.3.0]bicyclic diamine attached to the carbonylthrough one nitrogen, and is substituted with 0-2 R⁸ substituents;

or R¹³ is

R¹⁴ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, or benzyl;

R¹⁵ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, or benzyl;

or NR¹⁴R¹⁵ taken together is azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, N-(alkyl)piperazinyl, morpholinyl, thiomorpholinyl,homopiperidinyl, or homomorpholinyl;

R¹⁶ is hydrogen or alkyl;

R¹⁷ is hydrogen, alkyl, or cycloalkyl; and

X is methylene, a bond, or absent;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where:

R¹ is CO₂R⁵ or CONR⁶R⁷;

R² is furanyl, pyrrolyl, thienyl, pyrazolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, or tetrazolyl, and issubstituted with 0-2 substituents selected from oxo, amino, and alkyl,and 1 substituent selected from CO₂R⁵, CON(R¹²)₂, and COR¹³;

R³ is hydrogen, halo, alkyl, alkenyl, hydroxy, benzyloxy, or alkoxy;

R⁴ is cycloalkyl;

R⁵ is hydrogen or alkyl;

R⁶ is hydrogen, alkyl, alkylSO₂, cycloalkylSO₂, haloalkylSO₂,(R⁹)(R¹⁰)NSO₂, or (R¹¹)SO₂;

R⁷ is hydrogen or alkyl;

R⁸ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, alkylcarbonyl,cycloalkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl, alkylSO₂,cycloalkylSO₂, haloalkylSO₂, aminocarbonyl, (alkylamino)carbonyl,(dialkylamino)carbonyl, benzyl, benzyloxycarbonyl, or pyridinyl;

R⁹ is hydrogen or alkyl;

R¹⁰ is hydrogen or alkyl;

R¹¹ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,N-alkylpiperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl,homopiperazinyl, or homomorpholinyl;

R¹² is hydrogen, alkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl,(dialkylamino)alkyl, or (R¹¹)alkyl;

R¹³ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl,and is substituted with 0-3 substituents selected from alkyl, amino,alkylamino, dialkylamino, R¹¹, aminoalkyl, (alkylamino)alkyl,(dialkylamino)alkyl, or (R¹¹)alkyl;

or R¹³ is

or R¹³ is

or R¹³ is a [4.3.0] or [3.3.0]bicyclic diamine attached to the carbonylthrough one nitrogen, and is substituted with 0-2 R⁸ substituents;

or R¹³ is

R¹⁴ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, or benzyl;

R¹⁵ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, or benzyl;

or NR¹⁴R¹⁵ taken together is azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, N-(alkyl)piperazinyl, morpholinyl, thiomorpholinyl,homopiperidinyl, or homomorpholinyl;

R¹⁶ is hydrogen or alkyl;

R¹⁷ is hydrogen, alkyl, or cycloalkyl; and

X is methylene, a bond, or absent;

or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a compound of formula I where R¹ isCONR⁶R⁷; R⁶ is alkylSO₂, cycloalkylSO₂, haloalkylSO₂, (R⁹)₂NSO₂, or(R¹⁰)SO₂; and R⁷ is hydrogen.

Another aspect of the invention is a compound of formula I where R³ ishydrogen.

Another aspect of the invention is a compound of formula I where R³ ismethoxy.

Another aspect of the invention is a compound of formula I where R⁴ iscyclohexyl.

Another aspect of the invention is a compound of formula I where R⁶ isalkylSO₂, cycloalkylSO₂, (R⁹)(R¹⁰)NSO₂ or (R¹¹)SO₂.

Another aspect of the invention is a compound of formula I where R² ispyrazolyl substituted with 2 substituents selected from alkyl andhaloalkyl and 1 COR¹³ substituent R¹³ is

R⁸ is hydrogen or alkyl; R¹⁶ is hydrogen or alkyl; and R¹⁷ is alkyl.

Another aspect of the invention is a compound of formula I where X ismethylene.

Another aspect of the invention is a compound of formula I where X is abond.

Another aspect of the invention is a compound of formula I where X isabsent.

Another aspect of the invention is a compound of formula I according tothe following stereochemistry.

Another aspect of the invention is a compound of formula I according tothe following stereochemistry.

Another aspect of the invention is a compound of formula I according tothe following stereochemistry.

Another aspect of the invention is a compound of formula I according tothe following stereochemistry.

Any scope of any variable, including R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and X can be used independentlywith the scope of any other instance of a variable.

Unless specified otherwise, these terms have the following meanings.“Alkyl” means a straight or branched alkyl group composed of 1 to 6carbons. “Alkenyl” means a straight or branched alkyl group composed of2 to 6 carbons with at least one double bond. “Cycloalkyl” means amonocyclic ring system composed of 3 to 7 carbons. “Hydroxyalkyl,”“alkoxy” and other terms with a substituted alkyl moiety includestraight and branched isomers composed of 1 to 6 carbon atoms for thealkyl moiety. “Haloalkyl” and “haloalkoxy” include all halogenatedisomers from monohalo substituted alkyl to perhalo substituted alkyl.“Aryl” includes carbocyclic and heterocyclic aromatic substituents.Parenthetic and multiparenthetic terms are intended to clarify bondingrelationships to those skilled in the art. For example, a term such as((R)alkyl) means an alkyl substituent further substituted with thesubstituent R.

The invention includes all pharmaceutically acceptable salt forms of thecompounds. Pharmaceutically acceptable salts are those in which thecounter ions do not contribute significantly to the physiologicalactivity or toxicity of the compounds and as such function aspharmacological equivalents. These salts can be made according to commonorganic techniques employing commercially available reagents. Someanionic salt forms include acetate, acistrate, besylate, bromide,chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride,hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate,phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Somecationic salt forms include ammonium, aluminum, benzathine, bismuth,calcium, choline, diethylamine, diethanolamine, lithium, magnesium,meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium,tromethamine, and zinc.

Some of the compounds of the invention possess asymmetric carbon atoms(see, for example, the compound below). The invention includes allstereoisomeric forms, including enantiomers and diastereomers as well asmixtures of stereoisomers such as racemates. Some stereoisomers can bemade using methods known in the art. Stereoisomeric mixtures of thecompounds and related intermediates can be separated into individualisomers according to methods commonly known in the art.

The compounds may be made by methods known in the art including thosedescribed below. Some reagents and intermediates are known in the art.Other reagents and intermediates can be made by methods known in the artusing available materials. The variables (e.g. numbered “R”substituents) used to describe the synthesis of the compounds areintended only to illustrate how to make the compounds and are not to beconfused with variables used in the claims or in other sections of thespecification. Abbreviations used within the schemes generally followconventions used in the art.

The scheme shown below illustrates methods that can be used for makingintermediates and compounds.

Alternatively, the reaction sequence can be modified as shown below.

7H-Indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-(phenylsulfonyl)-, tert-butyl ester

To a solution of3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxylate (6.00g, 13.8 mmol) in dioxane (28.0 mL) and BEMP (7.97 mL, 27.6 mmol) wasadded phenyl vinyl sulfone (27.6 g, 2.21 mmol). The resulting mixturewas stirred in a sealed tube in a microwave at 120° C. for 15 min. Theresulting solution was concentrated under reduced pressure. Silica gelchromatography (CH₂Cl₂) of the concentrate afforded the title compound6.36 g (79%) as a yellow oil. MS m/z 584 (MH⁺). 1H NMR (500 MHz,CHLOROFORM-d) δ ppm 1.18-1.33 (1H, m), 1.34-1.45 (2H, m), 1.49-57 (1H,m), 1.64 (9H, s.), 1.74-1.82 (2H, m), 1.90-2.09 (4H, m), 2.73 (1H, m,),3.93 (3H, s), 4.38 (1H, broad d), 5.08 (1H, br. d), 7.09 (1H, d, J=2.75Hz), 7.12-7.18 (3H, m), 7.22 (1H, d, J=7.45 Hz), 7.30 (1H, s), 7.48 (1H,d, J=8.85 Hz), 7.54 (1H, dd, J=8.55, 1.22 Hz), 7.61 (2H, m), 7.67 (1H,d, J=8.55), 8.01 (1H, s).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester.1,1-dimethylethyl13-cyclohexyl-3-(methyloxy)-6-(tributylstannanyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-(phenylsulfonyl)-, 1,1-dimethylethyl ester(1.00 g, 1.71 mMol) was dissolved in 26 mL of benzene along withbis(tributyltin) (2.8 mL, 5.54 mMol), tributyltin hydride (136 uL, 0.513mMol) and triethylamine (1.05 mL, 7.5 mMol). The solution was spargedfor approximately for 10 minutes with nitrogen then2,2′-bisazoisobutyronitrile (AIBN) (96 mg, 0.58 mMol) added to thereaction. The reaction was heated to reflux under nitrogen for 2 hr. Thereaction was followed by LC-MS using the following HPLC conditions:Shimadzu Analytical HPLC using Discovery VP software: % A=5%acetonitrile, 95% water, 10 mmol Ammonium Acetate % B=95% acetonitrile,5% water, 10 mmol Ammonium Acetate; Initial % B=0; Final % B=100;Gradient=3 min; Runtime=10 min; Flow rate=5 ml/min; Wavelength=220 nm;Column=Waters Xterra, 3 mm×50 mm, S7. To the reaction was addedtributyltin hydride (0.45 mL, 1.7 mMol) and AIBN (95 mg, 0.58 mMol), thereaction heated to reflux for 2 hrs, and analyzed for progress. AIBN (99mg, 0.60 mMol) added to the reaction and the reaction heated to refluxunder for an additional 6 hrs using a timer. The reaction was analyzedby LC-MS for progress then tributyltin hydride (1.0 ml, 3.8 mMol) andAIBN (97 mg, 0.59 mMol) was added and the reaction heated to reflux for2 hrs 20 min. The reaction was analyzed by LC-MS and AIBN (97 mg, 0.59mMol) added to the reaction. The reaction was heated for 1 hr undernitrogen at reflux and the cooled and analyzed by LC-MS. Volatiles wereremoved in vacuuo from the reaction and the reaction was purified bycolumn chromatography using a C₁₈ packing of 190 g of YMC GEL ODS-A, 120A spherical 75 uM. The reaction residue (6.67 g of yellow oil) wasdissolved in a minimum of dichloromethane and the solution applied ontothe reverse phase column packed in 10% dichloromethane in acetonitrile.Initial elution was done using 10% dichloromethane in acetonitrilefollowed by elution with 15% dichloromethane in acetonitrile. Thechromatography was monitored by TLC using Whatman MKC18F reverse phase1″×3″ 200 uM thickness TLC plates eluting using 15% dichloromethane inacetonitrile. Compound observation was accomplished by UV lamp at 254 nmand iodine staining of TLC plates. Product fractions were collected andvolatiles removed in vacuuo to yield 647 mg (52%) as a pale yellow foam.1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.71-0.83 (m, 9H) 0.85-0.96 (m, 3H) 0.95-1.08 (m, 6H) 1.15-1.27 (m, 7H) 1.27-1.49 (m, 11H) 1.53 (s, 5H)1.60-1.67 (m, 9H) 1.68-1.82 (m, 2H) 1.84-1.96 (m, 1H) 1.96-2.16 (m, 3H)2.74-2.91 (m, 1H) 3.90 (s, 3H) 4.16-4.40 (m, 1H) 4.82-5.03 (m, 1H)6.72-6.90 (m, 2 H) 6.96 (dd, J=8.55, 2.44 Hz, 1H) 7.43 (d, J=8.55 Hz,1H) 7.66 (dd, J=8.39, 1.37 Hz, 1H) 7.81 (d, J=8.55 Hz, 1H) 8.04 (s, 1H)LC-MS: Shimadzu Analytical HPLC using Discovery VP software: % A=5%acetonitrile, 95% water, 10 mmol Ammonium Acetate % B=95% acetonitrile,5% water, 10 mmol Ammonium Acetate; Initial % B=0; Final % B=100;Gradient=3 min; Runtime=10 min; Flow rate=5 ml/min; Wavelength=220 nm;Column=Waters Xterra, 3 mm×50 mm, S7. Retention Time=4.2 min, MS m/z 734(MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester.1,1-dimethylethyl13-cyclohexyl-3-(methyloxy)-6-(tributylstannanyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate

An assembly of a three necked flask fitted with an argon bubbler, refluxcondenser and dropping funnel was flame dried and then cooled under astream of argon. The flask was then charged with benzene (5 mL) and7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-(phenylsulfonyl)-, 1,1-dimethylethyl ester 1(500 mg, 0.857 mmol). The resultant mixture was sonnicated under argonfor 5 min (to remove oxygen) and then heated under reflux. A solution oftri-N-butyltin hydride (0.459 ml, 1.713 mmol) and2,2′-azobis(2-methylpropionitrile (52.0 mg, 0.317 mmol) in degassedbenzene (5 mL) was then added to the dropping funnel. Approximately 2.5mL of this solution was added dropwise over a period of approximately 30min, and the resultant solution was left to stir under reflux for 1.5 h.The remaining solution was added dropwise, slowly over a period ofapproximately 30 min, and heating was continued for a further 1.5 h. Themixture was then evaporated under reduced pressure to remove volatiles.The residue was slurried in hexane and applied to a silica gel biotagecartridge and then loaded onto a silica gel column equilibrated in 100%hexanes. The product was then eluted using a step gradient of ethylacetate-hexane: 0-100%, then 2-98%, then 5-95%. Homogeneous fractionswere combined and evaporated to give yellow oil. This was placed underhigh vacuum overnight to give the title compound as a viscous yellowcolored oil. [373 mg, 57%]. The product was stored under nitrogen in arefrigerator.

tert-butyl13-cyclohexyl-6-(4-(ethoxycarbonyl)-1,3-oxazol-2-yl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate

1,1-dimethylethyl13-cyclohexyl-3-(methyloxy)-6-(tributylstannanyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(266 mg, 0.36 mMol) was dissolved in 3.4 mL of 1,4-dioxane in a 2 dramvial. Ethyl 2-chlorooxazole-4-carboxylate (83.4 mg, 0.47 mMol) wasdissolved in the reaction followed by the addition ofbis(triphenylphosphine)palladium(II) chloride (17.7 mg, 0.025 mMol). Thereaction was capped under nitrogen and heated in an oil bath at 100 Cfor 17 hrs, after which the reaction was cooled and the reactionprogress was measured by LC-MS. To the reaction mixture was addedbis(triphenylphosphine)palladium(II) chloride (10 mg, 0.014 mMol). Thereaction was capped under nitrogen and heated for an additional 5 hrs at100 C. The reaction was concentrated in vacuuo and the residue adsorbedonto silica gel purified by silica gel chromatography eluting with agradient of dichloromethane to 2% ethyl acetate in dichloromethane toyield 233 mg of a yellow solid product. 1H NMR (500 MHz, CHLOROFORM-D) δppm 1.13-1.37 (m, 4H) 1.37-1.44 (m, 4H) 1.46-1.55 (m, 1H) 1.64 (s, 9H)1.68-1.81 (m, 2H) 1.83-1.98 (m, 3H) 1.98-2.13 (m, 3H) 2.74-2.88 (m, 1H)3.91 (s, 3H) 4.34-4.48 (m, 3H) 5.84-6.00 (m, 1H) 7.00 (d, J=2.44 Hz, 1H)7.08 (dd, J=8.55, 2.75 Hz, 1H) 7.53 (d, J=8.85 Hz, 1H) 7.69 (dd, J=8.55,1.22 Hz, 1H) 7.74 (s, 1H) 7.82 (d, J=8.24 Hz, 1H) 8.21 (s, 1H) 8.30 (s,1H); LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A=10% methanol, 90% water, 0.1% trifluoroacetic acid % B=90% methanol,10% water, 0.1% trifluoroacetic acid; Initial % B=0; Final % B=100;Gradient=3 min; Runtime=5 min; Flow rate=5 ml/min; Wavelength=220 nm;Column=Phenomenex Luna 3.0 mm×50 mm S10; Retention Time=3.4 min, MS m/z583 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-2-oxazolyl]-3-methoxy-

tert-butyl13-cyclohexyl-6-(4-(ethoxycarbonyl)-1,3-oxazol-2-yl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(109 mg, 0.19 mMol) was dissolved in 2 mL of 1,2-dichloroethane and 2 mLof trifluoroacetic acid added to the reaction. The reaction was stirredat room temperature for 1.5 hrs. Volatiles were removed and the productdried in vacuuo to yield 102 mg of a yellow solid. 1H NMR (500 MHz,CHLOROFORM-D) δ ppm 1.11-1.37 (m, 4H) 1.42 (t, J=7.02 Hz, 4H) 1.48-1.62(m, 1H) 1.77 (d, J=10.07 Hz, 2H) 1.86-2.13 (m, 4H) 2.73-2.90 (m, 1H)2.98-3.39 (m, 6H) 3.92 (s, 3H) 4.30-4.53 (m, 3H) 5.87-6.03 (m, 1H) 7.02(d, J=2.44 Hz, 1H) 7.09 (dd, J=8.70, 2.59 Hz, 1H) 7.75 (s, 1H) 7.79 (dd,J=8.39, 1.37 Hz, 1H) 7.88 (d, J=8.55 Hz, 1H) 8.24 (s, 1H) 8.50 (s, 1H);LC-MS: Shimadzu Analytical HPLC using Discovery VP software: % A=5%acetonitrile, 95% water, 10 mmol Ammonium Acetate % B=95% acetonitrile,5% water, 10 mmol Ammonium Acetate; Initial % B=0; Final % B=100;Gradient=2 min; Runtime=3 min; Flow rate=5 ml/min; Wavelength=220 nm;Column=Phenomenex Luna 3.0 mm×50 mm S10; Retention Time=1.7 min, MS m/z525 (MH⁻).

Ethyl2-(13-cyclohexyl-10-(((dimethylamino)sulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1,3-oxazole-4-carboxylate

Ethyl2-(13-cyclohexyl-10-(((dimethylamino)sulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1,3-oxazole-4-carboxylate.7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-2-oxazolyl]-3-methoxy-(115 mg, 0.22mMol) was dissolved in 3 ml of anhydrous THF and1,1′-carbonyldiimidazole (61 mg, 0.38 mMol) added to the reaction. Thereaction was stirred under nitrogen for 1 hr 20 min at room temperaturethen heated to reflux under nitrogen for 45 minutes. The reaction wascooled and dimethylsulfamide (186 mg, 1.49 mMol) was added to thereaction followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (39 uL, 0.26mMol) (DBU). The reaction was heated at 55 C for 16 hrs under nitrogen.The reaction was partitioned between dichloromethane and 0.1M monosodiumphosphate. The dichloromethane extract was washed with 0.1M monosodiumphosphate then dried over sodium sulfate. Volatiles were removed invacuuo to yield 167 mg of crude yellow product. One-half of the crudesample was dissolved in a mixture of acetonitrile and methanol andpurified by reverse phase prep HPLC under the following conditions:Shimadzu preparative HPLC using Discovery VP software: % A=10%acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1%TFA; Initial % B=50; Final % B=100; Gradient=12 min; Runtime=17 min;Flow rate=25 ml/min; Wavelength=220 nm; Column=Waters Sunfire 19 mm×100mm. Product retention time=12.25 min to 17 min (tailing due tosolubility). Obtained 25.2 mg of amorphous yellow solid. 1H NMR (500MHz, CHLOROFORM-D) δ ppm 1.18-1.30 (m, 2H) 1.34-1.46 (m, 5H) 1.47-1.62(m, 1H) 1.70-1.85 (m, 2H) 1.86-2.21 (m, 4H) 2.72-2.92 (m, 1H) 3.07 (s,6H) 3.92 (s, 3H) 4.08-4.34 (m, 2H) 4.41 (q, J=7.2 Hz, 3H) 5.75-5.99 (m,1H) 7.02 (d, J=2.75 Hz, 1H) 7.10 (dd, J=8.70, 2.59 Hz, 1H) 7.45-7.65 (m,2H) 7.71 (s, 1H) 7.89 (d, J=8.55 Hz, 1H) 8.20 (s, 1H) 8.29 (s, 1H) 9.36(s, 1H); LC-MS: Shimadzu Analytical HPLC using Discovery VP software: %A=5% acetonitrile, 95% water, 10 mmol Ammonium Acetate % B=95%acetonitrile, 5% water, 10 mmol Ammonium Acetate; Initial % B=0; Final %B=100; Gradient=2 min; Runtime=4 min; Flow rate=5 ml/min; Wavelength=220nm; Column=Phenomenex Luna 3.0 mm×50 mm S10; Retention Time=1.9 min, MSm/z 631 (MH⁻), m/z 633 (MH⁺).

13-cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(4-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,3-oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide

Ethyl2-(13-cyclohexyl-10-(((dimethylamino)sulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1,3-oxazole-4-carboxylate(35.7 mg, 0.056 mMol) was dissolved in 0.6 ml of THF in a 2 dram vial.Tetrabutylammonium hydroxide (170 uL, 0.17 mMol) as a 1M solution inmethanol was added to the reaction. The reaction was capped and stirredfor 3 hrs at room temperature. The reaction was partitioned between 1Nhydrochloric acid and dichloromethane. The organic phase was washed with1N hydrochloric acid and dried over sodium sulfate. The material wasconcentrated to dryness, dried in vacuuo and used without furtherpurification. The hydrolysis product (0.056 mMol) was dissolved in 1 mLof DMF and TBTU (39 mg, 0.12 mMol) added. The reaction was stirred atroom temperature under nitrogen for approximately 50 minutes then addDMAP (37.9 mg, 0.31 mMol) was added followed by3-methyl-3,8-diaza-bicyclo[3.2.1]octane dihydrochloride (23 mg, 0.11mMol). The reaction was stirred for 4 hrs at room temperature undernitrogen atmosphere until complete, then added to 20 mL of water andextracted with dichloromethane, washed organic layer with water and dryover sodium sulfate to yield 50 mg of crude product. The product waspurified by Prep HPLC under the following conditions: Shimadzupreparative HPLC using Discovery VP software: % A=10% acetonitrile, 90%water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA; Initial %B=30; Final % B=100; Gradient=12 min; Runtime=20 min; Flow rate=25ml/min; Wavelength=220 nm; Column=Waters Sunfire 19 mm×100 mm. Productretention time=6.1 min. Product fractions were concentrated in vacuuo toyield 30.5 mg of the title compound as a trifluoroacetic acid salt. 1HNMR (500 MHz, CHLOROFORM-D) δ ppm 1.09-1.30 (m, 1H) 1.31-1.61 (m, 3H)1.68-1.85 (m, 2H) 1.87-2.20 (m, 5H) 2.26-2.44 (m, 2H) 2.51-2.66 (m, 1H)2.77-2.90 (m, 1H) 2.91-3.01 (m, 3H) 3.04 (s, 6H) 3.12 (d, J=11.90 Hz,1H) 3.23 (d, J=11.60 Hz, 1H) 3.78 (d, J=12.21 Hz, 1H) 3.94 (s, 3H) 4.24(d, J=13.12 Hz, 1H) 4.43 (d, J=14.34 Hz, 1H) 5.01 (d, J=5.80 Hz, 1H)5.13-5.47 (m, 1H) 5.85 (d, J=14.04 Hz, 1H) 6.02 (s, 1H) 7.03 (d, J=2.75Hz, 1H) 7.12 (dd, J=8.70, 2.59 Hz, 1H) 7.25-7.32 (m, 1H) 7.56 (d, J=8.55Hz, 1H) 7.69 (s, 1H) 7.88 (d, J=8.24 Hz, 1H) 8.18 (s, 1H) 8.28 (s, 1H)8.52 (s, 1H) 11.72 (s, 1H); LC-MS: Shimadzu Analytical HPLC usingDiscovery VP software: % A=5% acetonitrile, 95% water, 10 mmol AmmoniumAcetate % B=95% acetonitrile, 5% water, 10 mmol Ammonium Acetate;Initial % B=0; Final % B=100; Gradient=2 min; Runtime=3 min; Flow rate=5ml/min; Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10Retention Time=1.7 min, MS m/z 711 (MH⁻), m/z 713 (MH⁺).

13-Cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(4-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,3-oxazol-2-yl)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxamide

13-Cyclohexyl-N-((dimethylamino)sulfonyl)-3-methoxy-6-(4-((3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl)-1,3-oxazol-2-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide(26.5 mg, 0.037 mMol) was dissolved in 1 mL of THF and 0.3 mL ofmethanol added followed by 10 mg of 10% palladium on carbon. Thereaction was placed under hydrogen at 1 atmosphere (balloon) and stirredfor 18 hrs at room temperature. The reaction was filtered through acelite plug and rinsed with acetonitrile. Volatiles were removed fromthe filtrate in vacuuo and the residue was dissolved in acetonitrile andpurified by Prep HPLC under the following conditions: Shimadzupreparative HPLC using Discovery VP software: % A=10% acetonitrile, 90%water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA; Initial %B=30; Final % B=100; Gradient=12 min; Runtime=17 min; Flow rate=25ml/min; Wavelength=220 nm; Column=Waters Sunfire 19 mm×100 mm. Productretention time=5.3 minutes. The title compound was isolated as a TFAsalt, 17.6 mg obtained. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.20-1.33(m, 1.1H) 1.33-1.54 (m, 2.1H) 1.65 (t, J=10.99 Hz, 1.1H) 1.74-1.86 (m,1.9H) 1.89-2.11 (m, 5.6H) 2.11-2.44 (m, 3.0H) 2.71-2.86 (m, 3.2H)2.87-2.98 (m, 2.9H) 2.98-3.10 (m, 7.7H) 3.08-3.45 (m, 6.1H) 3.72-3.83(m, 0.9H) 3.82-3.93 (m, 3.1H) 3.92-4.00 (m, 0.8H) 4.05 (dd, J=14.80,5.65 Hz, 0.8H) 4.55-5.12 (m, 2.6H) 5.60 (d, J=12.82 Hz, 0.3H) 6.64-7.12(m, 2.0H) 7.29-7.62 (m, 1.8H) 7.77-7.97 (m, 1.2H) 7.97-8.43 (m, 1.2H)8.55-9.33 (m, 0.7H) 11.70 (s, 0.5H). LC-MS: Shimadzu Analytical HPLCusing Discovery VP software: % A=5% acetonitrile, 95% water, 10 mmolAmmonium Acetate % B=95% acetonitrile, 5% water, 10 mmol AmmoniumAcetate; Initial % B=0; Final % B=100; Gradient=3 min; Runtime=5 min;Flow rate=5 ml/min; Wavelength=220 nm; Column=Gemini 4.6 mm×50 mm S5;Retention Time=2.2 min, MS m/z 715 (MH⁺), m/z 713 (MH⁻).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[2-(methoxycarbonyl)-3-thienyl]-,1,1-dimethylethyl ester. 7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid, 13-cyclohexyl-3-methoxy-6-(tributylstannyl)-, 1,1-dimethylethylester (140 mg, 0.19 mMol) was dissolved in 2 mL of 1,4-dioxane alongwith methyl 3-bromothiophene-2-carboxylate (79 mg, 0.36 mMol) in a 2dram vial. To the reaction was added bis(triphenylphosphine)palladiumdichloride (9.2 mg, 0.013 mMol). The reaction was capped under anitrogen atmosphere and heated to 100 C for 4.5 hrs. The reaction wascooled and filtered through a 0.45 uM nylon syringe filter and thevolatiles removed in vacuuo to yield 226 mg of a yellow oil. The titlecompound was purified by silica gel chromatography eluting with 30%hexanes in dichloromethane to yield 73 mg (66%) of product. 1H NMR (500MHz, CHLOROFORM-D) δ ppm 0.92 (t, J=7.32 Hz, 2H) 1.24-1.44 (m, 6H) 1.57(s, 9 H) 1.58-1.71 (m, 2H) 1.77 (d, J=8.85 Hz, 2H) 1.85-1.99 (m, 1H)2.00-2.17 (m, 3H) 2.83-2.93 (m, 1H) 3.82 (s, 3H) 3.88 (s, 3H) 4.71 (s,1H) 5.10 (s, 1H) 6.80 (s, 1H) 6.83 (d, J=4.88 Hz, 1H) 6.90 (d, J=2.75Hz, 1H) 7.01 (dd, J=8.55, 2.75 Hz, 1H) 7.40 (d, J=5.19 Hz, 1H) 7.51 (d,J=8.85 Hz, 1H) 7.63 (dd, J=8.55, 1.22 Hz, 1H) 7.82 (d, J=8.55 Hz, 1H)7.88 (s, 1H); LC-MS: Shimadzu Analytical HPLC using Discovery VPsoftware: % A=10% methanol, 90% water, 0.1% trifluoroacetic acid % B=90%methanol, 10% water, 0.1% trifluoroacetic acid; Initial % B=0; Final %B=100; Gradient=2 min; Runtime=5 min; Flow rate=5 ml/min; Wavelength=220nm; Column=Phenomenex Luna 3.0 mm×50 mm S10; Retention Time=2.95 min, MSm/z 584 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,6-(2-carboxy-3-thienyl)-13-cyclohexyl-3-methoxy-,10-(1,1-dimethylethyl)ester

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[2-(methoxycarbonyl)-3-thienyl]-,1,1-dimethylethyl ester (65 mg, 0.11 mMol) was dissolved in 1 mL of THFin a 2 dram vial. To this solution was added 1.0M tetrabutylammoniumhydroxide (0.33 mL, 0.33 mMol) in methanol. The reaction was capped andstirred at room temperature for 3 hrs then monitored by HPLC. Additional1.0M tetrabutylammonium hydroxide (0.10 mL, 0.1 mMol) in methanol wasadded to the reaction and the reaction stirred capped at roomtemperature for an additional 21 hrs. The reaction was partitionedbetween dichloromethane and 0.1M citric acid. The aqueous phase wasextracted with dichloromethane and the organic extracts were combinedand dried over sodium sulfate. Volatiles were removed in vacuuo to yield72 mg of crude product. LC-MS: Shimadzu Analytical HPLC using DiscoveryVP software: % A=5% acetonitrile, 95% water, 10 mmol Ammonium Acetate %B=95% acetonitrile, 5% water, 10 mmol Ammonium Acetate; Initial % B=0;Final % B=100; Gradient=3 min; Runtime=5 min; Flow rate=5 ml/min;Wavelength=220 nm; Column=Phenomenex Luna 3.0 mm×50 mm S10; RetentionTime=2.50 min, MS m/z 570 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[2-[(diethylamino)carbonyl]-3-thienyl]-3-methoxy-,1,1-dimethylethyl ester

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,6-(2-carboxy-3-thienyl)-13-cyclohexyl-3-methoxy-,10-(1,1-dimethylethyl)ester (36 mg, 0.063 mMol) was dissolved in 0.7 mLof anhydrous DMF and TBTU (36.5 mg, 0.114 mMol) added to the reaction.The reaction was capped under nitrogen and stirred at room temperaturefor 1.5 hrs. DMAP (29 mg, 0.24 mMol) was then dissolved in the reactionthen diethyl amine (26 uL, 0.25 mMol) added. The reaction was cappedunder a nitrogen atmosphere and stirred for 21 hrs at room temperature.The reaction was added to 15 mL of water and the aqueous suspensionextracted with dichloromethane. The organic phase was washedsequentially with 0.1M citric acid, water and dried over sodium sulfate,filtered and volatiles removed in vacuuo to yield a amber oil. LC-MS:Shimadzu Analytical HPLC using Discovery VP software: % A=10% methanol,90% water, 0.1% trifluoroacetic acid % B=90% methanol, 10% water, 0.1%trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=5 min;Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=PhenomenexLuna 3.0 mm×50 mm S10; Retention Time=4.64 min, MS m/z 625 (MH⁺), 647(M+Na)⁺.

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[2-[(diethylamino)carbonyl]-3-thienyl]-3-methoxy-

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[2-[(diethylamino)carbonyl]-3-thienyl]-3-methoxy-,1,1-dimethylethyl ester (39 mg, 0.06 mMol) was dissolved in 1 mL of1,2-dichloroethane and 1 mL of trifluoroacetic acid was added. Thereaction was stirred at room temperature for 2 hrs then volatiles wereremoved in vacuuo. The reaction product was repeatedly dissolved inbenzene and volatiles removed in vacuuo to aid in the removal ofresidual TFA. Weight of product was 39 mg as an amorphous solid. LC-MS:Shimadzu Analytical HPLC using Discovery VP software: % A=5%acetonitrile, 95% water, 10 mmol Ammonium Acetate % B=95% acetonitrile,5% water, 10 mmol Ammonium Acetate; Initial % B=0; Final % B=100;Gradient=3 min; Runtime=5 min; Flow rate=5 ml/min; Wavelength=220 nm;Column=Phenomenex Luna 3.0 mm×50 mm S10; Retention Time=2.31, MS m/z 569(MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[2-[(diethylamino)carbonyl]-3-thienyl]-N-[(dimethylamino)sulfonyl]-3-methoxy-

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[2-[(diethylamino)carbonyl]-3-thienyl]-3-methoxy-(36.7mg, 0.064 mmol) was dissolved in THF (1 ml) and carbonyldiimidazole (19mg, 0.117 mmol) added to the reaction. The reaction was stirred under anitrogen atmosphere at room temperature for 1.5 hours. The reaction wasthen heated to 60 C for 1.5 hours, then cooled and dimethylsulfamide (55mg, 0.444 mmol) was added to the reaction followed by DBU (13.3 uL,0.089 mmol). The reaction was capped under a nitrogen atmosphere andheated at 65 C to 70 C overnight. The reaction was cooled thenpartitioned between dichloromethane and 1N aqueous hydrochloric acid.The aqueous phase was back extracted with dichloromethane and theorganic layers combined and washed sequentially with 1N aqueoushydrochloric acid, aqueous 0.1M NaH2PO4. The dichloromethane phase wasdried over sodium sulfate, filtered and volatiles removed in vacuuo toyield 47 mg of brown film. The sample was dissolved in acetonitrile/DMF(1:1) and purified using a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100mm column and monitored using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 25mL/min, a gradient of 50 solvent A/50% solvent B to 0% solvent A/100%solvent B, a gradient time of 15 minutes with a run time of 25 minutesusing % A=10% acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile,10% water, 0.1% TFA solvent system. Solvent was removed from the productfraction in vacuuo to yield 18.1 mg of an amorphous yellow solid. 1H NMR(500 MHz, CHLOROFORM-D) δ ppm 0.53 (br.s, 3H) 0.96 (br.s, 3H) 1.04-1.44(m, 4H) 1.51 (d, J=10.07 Hz, 1H) 1.78 (d, J=9.46 Hz, 2H) 1.88-2.13 (m,4H) 2.40-2.52 (m, 1H) 2.80-2.97 (m, 3 H) 3.05 (s, 6H) 3.57 (br.s, 1H)3.89 (s, 3H) 4.49 (d, J=14.65 Hz, 1H) 5.20 (d, J=14.04 Hz, 1H) 6.93 (d,J=2.75 Hz, 1H) 6.98 (s, 1H) 7.02 (dd, J=8.70, 2.59 Hz, 1H) 7.11 (d,J=5.19 Hz, 1H) 7.38 (d, J=4.88 Hz, 1H) 7.41-7.52 (m, 2H) 7.86 (d, J=8.55Hz, 1H) 8.01 (s, 1H) 9.18 (s, 1H); LC-MS retention time 2.19 min; 673m/z (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.

tert-Butyl13-cyclohexyl-3-methoxy-6-(2-(4-morpholinylcarbonyl)-3-thienyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate.In a 2 dram vial, 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,6-(2-carboxy-3-thienyl)-13-cyclohexyl-3-methoxy-,10-(1,1-dimethylethyl)ester (33.7 mg, 0.059 mmol) andO-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(34.2 mg, 0.106 mmol) was dissolved in DMF (0.7 ml) to give a clearyellow solution. The reaction was capped under a nitrogen atmosphere andstirred at room temperature for 1 hr 20 min. DMAP (28.9 mg, 0.237 mmol)was dissolved in the reaction then morpholine (10.5 μl, 0.121 mmol) wasadded. The reaction was capped under a nitrogen atmosphere and stirredat room temperature for 2 days. Pour reaction into 15 mL of water. Apale yellow precipitate forms. Extract into dichloromethane. Washdichloromethane solution with 0.1M aqueous citric acid, back extractaqueous using dichloromethane. Combine dichloromethane phases wash 1×with water and dry over sodium sulfate. Remove volatiles in vacuuo toyield 45 mg of the title product as a yellow oil. LC-MS: ShimadzuAnalytical HPLC using Discovery VP software: % A=10% methanol, 90%water, 0.1% trifluoroacetic acid % B=90% methanol, 10% water, 0.1%trifluoroacetic acid; Initial % B=50; Final % B=100; Gradient=6 min;Runtime=6 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=PhenomenexLuna 3.0 mm×50 mm S10; Retention Time=4.38 min, MS m/z 639 (MH⁺).

13-Cyclohexyl-3-methoxy-6-(2-(4-morpholinylcarbonyl)-3-thienyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid

In a 2 dram vial, dissolve tert-Butyl13-cyclohexyl-3-methoxy-6-(2-(4-morpholinylcarbonyl)-3-thienyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(37.7 mg, 0.059 mmol) in 1,2-Dichloroethane (1 mL) add TFA (1 mL, 12.98mmol) The reaction was capped under a nitrogen atmosphere and stirred atroom temperature for 1.5 hrs. Transfer reaction contents to a 25 mL pearflask using benzene to rinse. Remove volatiles in vacuuo. Dissolveproduct in benzene and rotovap to aid in trace TFA removal. Obtained 41mg of title compound as a yellow brown film. A LC-MS was obtained toconfirm product and the product used in the next step without furtherpurification. LC-MS: Shimadzu Analytical HPLC using Discovery VPsoftware: % A=5% acetonitrile, 95% water, 10 mmol Ammonium Acetate %B=95% acetonitrile, 5% water, 10 mmol Ammonium Acetate; Initial % B=0;Final % B=100; Gradient=3 min; Runtime=5 min; Flow rate=5 ml/min;Wavelength=220 nm; Column=Waters Xterra, 3 mm×50 mm, S7. RetentionTime=1.73 min, MS m/z 583 (MH⁺), m/z 581 (M−H)⁻.

13-Cyclohexyl-N-(dimethylsulfamoyl)-3-methoxy-6-(2-(4-morpholinylcarbonyl)-3-thienyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide

In a 2 dram vial, dissolve13-Cyclohexyl-3-methoxy-6-(2-(4-morpholinylcarbonyl)-3-thienyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid (38 mg, 0.065 mmol) in 1 mL of anhydrous THF, add CDI (19.03 mg,0.117 mmol) to the reaction. The reaction was capped under a nitrogenatmosphere and stirred at room temperature for approximately 1 hour. Thereaction was heated capped under nitrogen at 65 C for 1 hour, thencooled to room temperature and N,N-Dimethylsulfamide (44.3 mg, 0.357mmol) then DBU (13.8 μL, 0.092 mmol) added to the reaction. The reactionwas capped and heated under nitrogen over night at 65° C. Analysis of analiquot by LC-MS indicated that the reaction was incomplete. To thereaction was added more dimethylsulfamide (19 mg, 0.153 mmol) and DBU(13.8 uL, 0.092 mmol). The reaction was capped under a nitrogenatmosphere and heated at 69 C for 3.25 hrs. Analysis of the reaction byLC-MS indicated that the reaction was complete. The reaction waspartitioned between dichloromethane and 1N aqueous hydrochloric acid.The aqueous layer was extracted with dichloromethane. The organic layerswere combined and washed sequentially with 1N aqueous hydrochloric acidthen 0.1M sodium dihydrogen phosphate (NaH₂PO₄) and dried over sodiumsulfate. Volatiles were removed in vacuuo to give a yellow oil/film. Thecrude title compound was dried in vacuuo overnight at room temperature.Weight of crude product is 43 mg as a yellow/brown solid. Dissolve in amixture of acetonitrile and DMF and purify by reverse phase HPLC underthe following conditions: Shimadzu Preparative HPLC running Discovery VPsoftware, % A=10% acetonitrile, 90% water, 0.1% TFA % B=90%acetonitrile, 10% water, 0.1% TFA; Initial % B=50; Final % B=100;Gradient=15 min; Runtime=25 min; Flow rate=25 ml/min; Wavelength=220 nm;Column=Waters Sunfire 19 mm×100 mm. Product collection time=9.72 min. to10.49 min. Volatiles were removed in vacuuo from the product fraction toyield 14.2 mg of the title compound as a yellow solid. 1H NMR (500 MHz,CHLOROFORM-D) δ ppm 1.17-1.30 (m, 1H) 1.32-1.50 (m, 2H) 1.55 (d, J=11.29Hz, 1H) 1.78 (d, J=10.99 Hz, 2H) 1.90-2.16 (m, 4 H) 2.42-2.58 (m, 1H)2.60-2.86 (m, 4H) 2.85-2.94 (m, 2H) 2.95-3.04 (m, 2H) 3.06 (s, 6H)3.10-3.30 (m, 1H) 3.91 (s, 3H) 4.56 (d, J=14.65 Hz, 1H) 5.09 (d, J=14.65Hz, 1H) 6.87 (s, 1H) 6.93 (d, J=2.75 Hz, 1H) 7.05 (dd, J=8.70, 2.59 Hz,1 H) 7.08 (d, J=4.88 Hz, 1H) 7.45 (d, J=4.88 Hz, 1H) 7.47-7.54 (m, 2H)7.83 (s, 1H) 7.91 (d, J=8.55 Hz, 1H) 9.59 (s, 1H). LC-MS: ShimadzuAnalytical HPLC using Discovery VP software: % A=5% acetonitrile, 95%water, 10 mmol Ammonium Acetate % B=95% acetonitrile, 5% water, 10 mmolAmmonium Acetate; Initial % B=0; Final % B=100; Gradient=3 min;Runtime=4 min; Flow rate=5 ml/min; Wavelength=220 nm; Column=WatersXterra, 3 mm×50 mm, S7. Retention Time=2.05 min min, MS m/z 689 (MH⁺),m/z 687 (M−H)⁻.

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-2-(methylthio)-5-thiazolyl]-3-methoxy-,1,1-dimethylethyl ester

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester(203 mg, 0.277 mmol) was dissolved in 1,4-dioxane (2.7 ml)) in a 2-5 mLtapered microwave vessel with magnetic stir bar. To the reaction wasadded ethyl 5-bromo-2-(methylthio)thiazole-4-carboxylate (171 mg, 0.606mmol), and bis(triphenylphosphine)palladium(II) chloride (14.9 mg, 0.021mmol). The reaction was capped under a nitrogen atmosphere and heated to100 C for 17.5 hrs. HPLC analysis of the reaction indicated onlyapproximately 45% conversion of starting material. Additional catalystbis(triphenylphosphine)palladium(II) chloride (5.7 mg) was added to thereaction and the reaction was heated under a nitrogen atmosphere at 110C for 23 hrs. Volatiles were removed from the reaction mixture in vacuuoand the crude reaction mixture was dissolved in a 8 ml of aDMF/acetonitrile mixture and purified as four 2 mL injections usingreverse phase HPLC. The sample was purified on a Shimadzu high pressureliquid chromatography system employing Discovery VP software interfacedwith a SCL-10A controller, SIL-10A autosampler and FRC-10A fractioncollector. The sample was dissolved in acetonitrile and DMF purifiedusing a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column andmonitored using a SPD-10AV UV-Vis detector at a detector wave length of220 nM. The elution conditions employed a flow rate of 25 mL/min, agradient of 40% solvent A/60% solvent B to 0% solvent A/100% solvent B,a gradient time of 15 minutes with a run time of 30 minutes using %A=10% acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water,0.1% TFA solvent system. Retention time of product=26.6 min. Volatilesfrom the product fractions were removed in vacuuo using a speed vac at amedium heating setting.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.16-1.26 (m, 1H) 1.30 (t, J=7.02Hz, 3H) 1.33-1.56 (m, 3H) 1.60 (s, 10H) 1.63-1.83 (m, 5H) 1.94 (br.s,1H) 1.98-2.16 (m, 3H) 2.71 (s, 3H) 2.82-2.92 (m, 1H) 3.90 (s, 3H) 4.28(q, J=7.02 Hz, 2 H) 4.53 (d, J=14.95 Hz, 1H) 5.52 (d, J=14.65 Hz, 1H)6.98 (d, J=2.75 Hz, 1H) 7.03 (dd, J=8.85, 2.75 Hz, 1H) 7.49-7.54 (m, 2H)7.65 (dd, J=8.55, 1.53 Hz, 1H) 7.81 (d, J=8.55 Hz, 1H) 8.13 (d, J=1.22Hz, 1H).

LC-MS retention time 3.08 min; 645 m/z (MH⁺). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

The scheme shown below is illustrative of methods that can be used tomake intermediates and compounds.

10-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylicacid

Dissolve 10-(1,1-dimethylethyl) 6-methyl13-cyclohexyl-3-(methyloxy)-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate(5.53 g, 11.02 mmol) in THF (70 ml) with heating, add DMF (20 ml) tomaintain solubility, allow to cool to room temperature then addtetrabutylammonium hydroxide (33.1 ml, 33.1 mmol) 1.0M in methanol. Stirreaction at room temperature for 2 hrs then add 0.1N aqueous 0.1Nhydrochloric acid to the reaction followed by 01M aqueous NaH2PO4.Separate phases, wash organic layer sequentially with 1.0N aqueoushydrochloric acid, 0.1M aqueous NaH2PO4. Back extract aqueous 1× usingethyl acetate. Combine ethyl acetate fractions and wash sequentiallywith 0.1M aqueous NaH2PO4 and brine. Dry over magnesium sulfate, filterand remove solvents in vacuuo to yield a bright yellow solid. Dryproduct in vacuuo at room temperature to give 5.21 g (97%). 1H NMR (500MHz, CHLOROFORM-D) δ ppm 1.12-1.28 (m, 2 H) 1.28-1.45 (m, 2H) 1.46-1.60(m, 2H) 1.63 (s, 9H) 1.66-1.96 (m, 4H) 1.96-2.16 (m, 3H) 2.76-2.84 (m,1H) 3.91 (s, 3H) 4.18 (br.s., 1H) 5.66 (br.s, 1H) 7.00 (d, J=2.44 Hz,1H) 7.10 (dd, J=8.55, 2.75 Hz, 1H) 7.53 (d, J=8.54 Hz, 1H) 7.65-7.71 (m,1H) 7.82 (d, J=8.24 Hz, 1H) 7.93 (s, 1H) 8.22 (s, 1H). LC-MS retentiontime 1.47 min; 486 m/z (MH−). LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 5 ml/min, a gradientof 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, agradient time of 2 min, a hold time of 1 min, and an analysis time of 3min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetateand solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MSdata was determined using a Micromass Platform for LC in electrospraymode.

tert-Butyl13-cyclohexyl-3-methoxy-6-(4-(methoxycarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate.10-(tert-butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylicacid (1.00 g, 2.051 mmol) was dissolve in DMF (10 ml) and potassiumcarbonate (0.624 g, 4.51 mmol) was added to the reaction followed bymethyl isocyanoacetate (0.24 ml, 2.64 mmol). The reaction was stirredunder a nitrogen atmosphere at room temperature for approximately 5minutes then cooled to 0 C. Diphenylphosphoryl azide (0.5 ml, 2.320mmol) was slowly added to the reaction over 10 minutes. The reaction wasstirred at 0 C under a nitrogen atmosphere and allowed to slowly warm toroom temperature overnight. Dilute reaction. with 100 ml ofbenzene/ethyl acetate (1:1) and wash with water. Back extract aqueouslayer using ethyl acetate. Combine organic extracts and washsuccessively with 0.1M aqueous citric acid, saturated aqueous sodiumbicarbonate and then brine and dry over magnesium sulfate. Filter andremove volatiles in vacuuo. Chromatograph on 43.4 g of silica gel slurrypacked in 5% ethyl acetate/dichloromethane. Elute with 5% ethylacetate/dichloromethane. Combination of pure product fractions andremoval of volatiles in vacuuo yielded 215 mg of an amorphous yellowsolid. Combination of less pure fractions yielded an additional 189 mgof product with purity greater than 92%. 1H NMR (500 MHz, CHLOROFORM-D)δ ppm 1.11-1.29 (m, 2H) 1.30-1.48 (m, 3H) 1.57 (s, 2H) 1.61 (s, 10H)1.69-1.80 (m, 2H) 1.86-1.98 (m, 1H) 1.99-2.13 (m, 4H) 2.76-2.90 (m, 1H)3.92 (s, 3H) 3.98 (s, 3H) 4.47 (d, J=12.82 Hz, 1H) 5.84 (d, J=14.65 Hz,1H) 7.02 (d, J=2.44 Hz, 1H) 7.07 (dd, J=8.55, 2.75 Hz, 1H) 7.53 (d,J=8.55 Hz, 1H) 7.65-7.71 (m, 1H) 7.82 (d, J=8.24 Hz, 1H) 7.87 (s, 1H)8.08 (s, 1H) 8.16 (s, 1H). LC-MS retention time 2.75 min; m/z (MH+). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, ahold time of 0 min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

5-(10-(tert-Butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1,3-oxazole-4-carboxylicacid

tert-Butyl13-cyclohexyl-3-methoxy-6-(4-(methoxycarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(205 mg, 0.360 mmol) was dissolved in THF (3.0 ml) andtetrabutylammonium hydroxide (1.1 mL, 1.100 mmol) (1.0M in methanol) wasadded to the reaction. The reaction was capped and stirred at roomtemperature for 2 hrs. A 0.1M aqueous solution of NaH2PO4 was added tothe reaction followed by 0.1N aqueous hydrochloric acid. The product wasextracted into ethyl acetate and the organic phase washed sequentiallywith 0.1N aqueous hydrochloric acid, 0.1M aqueous NaH2PO4, brine anddried over magnesium sulfate. The product solution was filtered, solventremoved and product dried in vacuuo to yield 191 mg of a yellow solid.1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.77-0.94 (m, 1H) 1.12-1.31 (m, 3H)1.30-1.59 (m, 5H) 1.62 (s, 9H) 1.76 (d, J=11.29 Hz, 2H) 1.87-2.18 (m,4H) 2.76-2.90 (m, 1H) 3.91 (s, 3H) 4.45 (d, J=14.04 Hz, 1H) 6.03 (d,J=12.21 Hz, 1H) 7.03 (d, J=2.44 Hz, 1H) 7.08 (dd, J=8.55, 2.75 Hz, 1H)7.53 (d, J=8.85 Hz, 1H) 7.68 (d, J=8.24 Hz, 1H) 7.82 (d, J=8.55 Hz, 1H)7.91 (s, 1H) 8.21 (d, J=5.80 Hz, 2H). LC-MS retention time 1.86 min; m/z553 (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.

tert-Butyl13-cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate

5-(10-(tert-Butoxycarbonyl)-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl)-1,3-oxazole-4-carboxylicacid (185 mg, 0.334 mmol) was dissolved in DMF (3.2 ml), andO-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium tetrafluoroborate (193mg, 0.600 mmol) was added. The reaction was stirred capped at roomtemperature for 25 minutes and DMAP (163 mg, 1.334 mmol) was dissolvedin the reaction then morpholine (0.058 ml, 0.667 mmol) was added. Thereaction was capped and stirred at room temperature overnight. Thereaction was poured into 30 ml of water and extracted withdichloromethane. The organic layer was washed sequentially with 0.1Maqueous citric acid, 0.1M aqueous NaH2PO4, then dried over anhydroussodium sulfate. The sample was filtered, volatiles removed and thesample dried in vacuuo to obtain 227 mg of an amorphous orange solid. 1HNMR (500 MHz, CHLOROFORM-D) δ ppm 1.16-1.50 (m, 7H) 1.53-1.61 (m, 6H)1.62 (s, 10H) 1.76 (d, J=10.38 Hz, 2H) 1.83-2.15 (m, 5H) 3.40-3.84 (m,7H) 3.83-3.95 (m, 5H) 4.40 (d, J=11.60 Hz, 1H) 5.64 (d, J=12.21 Hz, 1H)6.97 (d, J=2.75 Hz, 1H) 7.05 (dd, J=8.39, 2.59 Hz, 1H) 7.50 (d, J=8.55Hz, 1H) 7.53 (s, 1H) 7.65 (d, J=8.24 Hz, 1H) 7.77-7.86 (m, 2H) 7.97-8.04(m, 1H) 8.10 (s, 1H). LC-MS retention time 2.64 min m/z 624 (MH+). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, ahold time of 2 min, and an analysis time of 5 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

13-Cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid

Dissolve tert-Butyl13-cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(203 mg, 0.325 mmol) in 1,2-dichloroethane (3 ml) add TFA (3 ml, 38.9mmol), The reaction was capped under a nitrogen atmosphere at 25° C. for2 hrs. Reaction volatiles were removed in vacuuo and the residuedissolved in 80 mL of ethyl acetate with heating. The solution waswashed with 1N aqueous hydrochloric acid (2×40 mL), brine and dried overmagnesium sulfate. The product solution was filtered, volatiles removedand the sample dried in vacuuo at room temperature overnight to give 179mg (97%) of a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm0.74-1.03 (m, 4 H) 1.06-1.31 (m, 6H) 1.32-1.50 (m, 3H) 1.56 (d, J=9.16Hz, 2H) 1.77 (d, J=8.85 Hz, 2H) 1.86-2.18 (m, 5H) 2.83-2.91 (m, 1H) 3.60(s, 3H) 3.64-3.89 (m, 4H) 3.88-3.93 (m, 4H) 3.95-4.08 (m, 1H) 4.43 (d,J=15.56 Hz, 1H) 5.64 (d, J=14.95 Hz, 1H) 6.99 (d, J=2.75 Hz, 1H) 7.07(dd, J=8.70, 2.59 Hz, 1H) 7.48-7.56 (m, 2 H) 7.85-7.94 (m, 2H) 8.15 (s,1H). LC-MS retention time 1.65 min; 568 m/z (MH+). LC data was recordedon a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XterraMS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0%solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1min, and an analysis time of 4 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

13-Cyclohexyl-N-(dimethylsulfamoyl)-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide

In a 2 dram vial,13-Cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid (40 mg, 0.070 mmol) in THF (1 ml) and CDI (23.8 mg, 0.147 mmol) wasadded to the reaction. The reaction was capped under a nitrogenatmosphere and stirred at room temperature for 1 hr. The reaction wasthen heated at 60 C for 1 hr, cooled and N,N-Dimethylsulfamide (46.5 mg,0.375 mmol) was added to the reaction followed by DBU (0.014 ml, 0.092mmol). The reaction was capped under a nitrogen atmosphere and heatedovernight (16 hrs) at 60 C. The reaction was monitored by HPLC andadditional N,N-Dimethylsulfamide (22.9 mg, 0.184 mmol) and DBU (0.015ml, 0.099 mmol) was added and the reaction heated to 70 C under anitrogen atmosphere for 5 hrs. The reaction mixture was partitionedbetween 1N aqueous hydrochloric acid and dichloromethane. The organicphase was washed sequentially with 1N aqueous hydrochloric acid and 0.1Maqueous NaH2PO4 and dried over sodium sulfate. Solvent was removed invacuuo to yield 46 mg of crude product. The title compound was purifiedon a Shimadzu high pressure liquid chromatography system employingDiscovery VP software and interfaced with a SCL-10A controller, SIL-10Aautosampler and FRC-10A fraction collector. The sample was dissolved inacetonitrile/DMF (1:1) and purified using a Waters Sunfire Prep C18 OBD,5 uM 19 mm×100 mm column and monitored using a SPD-10AV UV-Vis detectorat a detector wave length of 220 nM. The elution conditions employed aflow rate of 25 mL/min, a gradient of 70 solvent A/30% solvent B to 0%solvent A/100% solvent B, a gradient time of 12 minutes with a run timeof 20 minutes using % A=10% acetonitrile, 90% water, 0.1% TFA % B=90%acetonitrile, 10% water, 0.1% TFA solvent system. 1H NMR (500 MHz,CHLOROFORM-D) δ ppm 1.05-1.28 (m, 1.2H) 1.29-1.62 (m, 3.7H) 1.64-1.84(m, 4.0H) 1.84-2.20 (m, 4.6H) 2.47 (d, J=14.04 Hz, 0.1H) 2.78-2.88 (m,1.1H) 3.04 (s, 5.9H) 3.10 (s, 0.9H) 3.35-3.89 (m, 9.0H) 3.91 (s, 3.0H)4.09 (s, 0.4H) 4.18 (d, J=1.83 Hz, 0.9H) 4.41 (d, J=15.56 Hz, 0.9H) 4.55(d, J=16.48 Hz, 0.1H) 5.59 (d, J=14.95 Hz, 0.9H) 6.62 (d, J=14.34 Hz,0.1H) 6.97 (d, J=2.44 Hz, 1.0H) 7.07 (dd, J=8.70, 2.59 Hz, 1.0H)7.27-7.36 (m, 0.3H) 7.46-7.54 (m, 1.9H) 7.59 (d, J=8.55 Hz, 0.9H) 7.75(d, J=7.93 Hz, 0.1H) 7.82 (s, 1.0H) 7.87 (d, J=8.54 Hz, 0.9H) 8.15 (s,0.1H) 8.28-8.35 (m, 0.2H) 8.44 (s, 0.9H) 8.94 (d, J=9.16 Hz, 0.1H) 9.43(s, 0.9H) 9.88 (s, 0.1H) 12.11 (s, 0.1H). LC-MS retention time 1.40 min;672 m/z (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.

13-cyclohexyl-N-(isopropylsulfonyl)-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide

13-Cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid (40.8 mg, 0.072 mmol) was dissolved in THF (1 ml) and CDI (26 mg,0.160 mmol) added to the reaction. The reaction was capped under anitrogen atmosphere and stirred at room temperature for 50 min thenheated in an oil bath at 60 C for 1.5 hrs. The reaction was cooled andpropane-2-sulfonamide (46 mg, 0.373 mmol) was added to the reactionfollowed by DBU (0.022 ml, 0.144 mmol). The reaction was capped under anitrogen atmosphere and heated at 65 C overnight (16 hr). The reactionwas partitioned between dichloromethane and 1.0N aqueous hydrochloricacid. The organic layer was washed sequentially with 1N aqueoushydrochloric acid, 0.1M aqueous NaH2PO4. The organic layer was driedover sodium sulfate and solvent removed in vacuuo to yield 50 mg of anamorphous yellow solid. The title was purified on a Shimadzu highpressure liquid chromatography system employing Discovery VP softwareinterfaced with a SCL-10A controller, SIL-10A autosampler and FRC-10Afraction collector. The sample was dissolved in acetonitrile/DMF (1:1)purified using a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm columnand monitored using a SPD-10AV UV-Vis detector at a detector wave lengthof 220 nM. The elution conditions employed a flow rate of 25 mL/min, agradient of 70 solvent A/30% solvent B to 0% solvent A/100% solvent B, agradient time of 12 minutes with a run time of 15 minutes using % A=10%acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1%TFA solvent system. Removal of solvents and drying in vacuuo yielded28.3 mg of a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm1.15-1.28 (m, 1.2H) 1.29-1.60 (m, 10.9H) 1.59-1.85 (m, 6.7H) 1.86-2.15(m, 4.7H) 2.78-2.87 (m, 1.0H) 3.37-3.50 (m, 1.4H) 3.51-3.89 (m, 7.3H)3.91 (s, 3.3H) 4.02-4.12 (m, 1.5H) 4.15-4.26 (m, 0.9H) 4.42 (d, J=13.73Hz, 0.9H) 4.54 (d, J=15.26 Hz, 0.1H) 5.54 (d, J=14.65 Hz, 0.9H) 6.57 (d,J=14.04 Hz, 0.1H) 6.97 (d, J=2.44 Hz, 0.9H) 7.07 (dd, J=8.55, 2.44 Hz,1.0H) 7.28-7.35 (m, 0.3H) 7.48-7.54 (m, 2.0H) 7.62-7.67 (m, 1.0H) 7.75(d, J=7.93 Hz, 0.1H) 7.82 (s, 1.0H) 7.87 (d, J=8.55 Hz, 1.0H) 8.21 (s,0.9H) 8.31 (s, 0.2H) 8.48 (s, 1.0H) 8.94 (d, J=9.15 Hz, 0.1H) 9.46 (s,0.9H) 9.86 (s, 0.1H). LC-MS retention time 1.26 min; 671 m/z (MH−). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, ahold time of 1 min, and an analysis time of 3 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

13-cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-N-(4-morpholinylsulfonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide

13-Cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid (40.8 mg, 0.072 mmol) was dissolved in THF (1 ml) and CDI (26 mg,0.160 mmol) added to the reaction. The reaction was capped under anitrogen atmosphere and stirred at room temperature for 50 min thenheated in an oil bath at 60 C for 1.5 hrs. The reaction was cooled andpropane-2-sulfonamide (46 mg, 0.373 mmol) was added to the reactionfollowed by DBU (0.022 ml, 0.144 mmol). The reaction was capped under anitrogen atmosphere and heated at 65 C overnight (16 hr). The reactionwas partitioned between dichloromethane and 1.0N aqueous hydrochloricacid. The organic layer was washed sequentially with 1N aqueoushydrochloric acid, 0.1M aqueous NaH2PO4. The organic layer was driedover sodium sulfate and solvent removed in vacuuo to yield 50 mg of anamorphous yellow solid. The title was purified on a Shimadzu highpressure liquid chromatography system employing Discovery VP softwareinterfaced with a SCL-10A controller, SIL-10A autosampler and FRC-10Afraction collector. The sample was dissolved in acetonitrile/DMF (1:1)purified using a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm columnand monitored using a SPD-10AV UV-Vis detector at a detector wave lengthof 220 nM. The elution conditions employed a flow rate of 25 mL/min, agradient of 70 solvent A/30% solvent B to 0% solvent A/100% solvent B, agradient time of 12 minutes with a run time of 15 minutes using % A=10%acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1%TFA solvent system. Removal of solvents and drying in vacuuo yielded28.3 mg of a yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm1.15-1.28 (m, 1.3H) 1.30-1.46 (m, 2.4H) 1.48-1.61 (m, J=16.48 Hz, 1.2H)1.77 (d, J=9.77 Hz, 2.3H) 1.87-2.15 (m, 4.8H) 2.22-2.52 (m, 4.6H)2.78-2.90 (m, 1.1H) 3.37-3.72 (m, 8.9H) 3.76 (s, 6.2H) 3.80-3.89 (m,3.2H) 3.91 (s, 3.6H) 4.08 (s, 0.3H) 4.13-4.23 (m, 1.0H) 4.42 (d, J=13.73Hz, 0.9H) 4.65 (d, J=14.95 Hz, 0.1H) 5.55 (d, J=14.04 Hz, 1.0H) 6.97 (d,J=2.44 Hz, 1.0H) 7.07 (dd, J=8.70, 2.59 Hz, 1.0H) 7.27-7.33 (m, 0.2H)7.38 (s, 0.1H) 7.46-7.55 (m, 2.0H) 7.60 (d, J=9.77 Hz, 1.0H) 7.78 (d,J=8.24 Hz, 0.1H) 7.83 (s, 1.0H) 7.87 (d, J=8.55 Hz, 1H) 8.07 (s, 0.1H)8.10 (d, J=4.27 Hz, 0.1H) 8.31 (d, J=8.54 Hz, 0.1H) 8.42 (s, 0.9H) 8.94(d, J=9.16 Hz, 0.1H) 9.55 (s, 0.9H) 9.60 (s, 0.1H). LC-MS retention time1.63 min; 714 m/z (MH−). LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 5 ml/min, a gradientof 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, agradient time of 3 min, a hold time of 1 min, and an analysis time of 4min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetateand solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MSdata was determined using a Micromass Platform for LC in electrospraymode.

13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide

13-Cyclohexyl-3-methoxy-6-(4-(4-morpholinylcarbonyl)-1,3-oxazol-5-yl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid (40 mg, 0.070 mmol) was dissolved in THF (1 ml) and CDI (26 mg,0.160 mmol) added to the reaction. The reaction was capped under anitrogen atmosphere and stirred at room temperature for 1 hr 50 min thenheated in an oil bath at 65 C for 1 hr 10 min. The reaction was cooledand cyclopropanesulfonamide (48 mg, 0.396 mmol) then DBU (0.022 ml,0.146 mmol) was added to the reaction. The reaction was capped under anitrogen atmosphere and heated at 68 C overnight (18 hr). The reactionwas partitioned between dichloromethane and 1.0N aqueous hydrochloricacid. The organic layer was washed sequentially with 1N aqueoushydrochloric acid, 0.1M aqueous NaH2PO4. The organic layer was driedover sodium sulfate and solvent removed in vacuuo to yield 62 mg of anamorphous yellow solid. The title was purified on a Shimadzu highpressure liquid chromatography system employing Discovery VP softwareinterfaced with a SCL-10A controller, SIL-10A autosampler and FRC-10Afraction collector. The sample was dissolved in acetonitrile/DMF (1:1)purified using a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm columnand monitored using a SPD-10AV UV-Vis detector at a detector wave lengthof 220 nM. The elution conditions employed a flow rate of 25 mL/min, agradient of 70 solvent A/30% solvent B to 0% solvent A/100% solvent B, agradient time of 15 minutes with a run time of 20 minutes using % A=10%acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1%TFA solvent system. Removal of solvents and drying in vacuuo yielded30.8 mg of the title compound as a yellow amorphous solid. 1H NMR (500MHz, CHLOROFORM-D) δ ppm 0.99-1.28 (m, 4.0H) 1.29-1.45 (m, 3.9H)1.47-1.68 (m, 7.9H) 1.75 (m, 2.3H) 1.84-2.17 (m, 4.5H) 2.77-2.88 (m,1.0H) 3.14-3.23 (m, 1.2H) 3.33-3.89 (m, 8.3H) 3.91 (s, 3.3H) 4.09 (s,0.5H) 4.17 (s, 0.9H) 4.42 (d, J=14.34 Hz, 0.9H) 5.54 (d, J=15.56 Hz,0.9H) 6.60 (d, 0.1H) 6.97 (d, J=2.44 Hz, 1.0H) 7.07 (dd, J=8.55, 2.75Hz, 1.0H) 7.27-7.35 (m, 0.3H) 7.49 (s, 1.0H) 7.52 (d, J=8.85 Hz, 1.0H)7.64 (dd, J=8.55, 1.53 Hz, 1.0H) 7.75 (d, J=7.94 Hz, 0.2H) 7.82 (s,1.0H) 7.87 (d, J=8.55 Hz, 1.0H) 8.21 (s, 0.1H) 8.31-8.36 (m, 0.3H) 8.43(d, J=1.53 Hz, 1.0H) 8.95 (d, J=9.16 Hz, 0.2H) 9.61 (s, 1.0H) 9.82 (s,0.1H). LC-MS retention time 1.59 min; 669 m/z (MH−). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, ahold time of 1 min, and an analysis time of 4 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

The scheme depicted below is illustrative of methods that can be used tomake intermediates and compounds.

An additional variation in the methodology that can be employed for thesynthesis of intermediates and compounds is shown in the followingscheme.

A further variation of the methodology that can be used for thesynthesis of further intermediates and compounds is depicted the schemeshown below.

tert-Butyl6-acetyl-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate

To a suspension of tert-butyl3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxylate (2 g,4.61 mmol) in dioxane (9.2 mL) add2-tert-butylimino-2-diethylamino-1,3-di-methylperhydrodiazaphosphorine(2.00 mL, 6.92 mmol) then but-3-en-2-one (0.756 mL, 9.23 mmol) in a 20ml microwave vessel. Cap the heterogenous reaction under nitrogen andheat in the microwave at 120 C for 40 minutes. This reaction wasrepeated two more times on the above scale and one last time withtert-butyl3-cyclohexyl-2-(2-formyl-4-methoxyphenyl)-1H-indole-6-carboxylate (2.51g, 5.79 mmol) dissolved in dioxane (11.5 ml), add BEMP (2.5 ml, 8.64mmol) followed by but-3-en-2-one (0.95 ml, 11.46 mmol). Each reactionsegment was worked up while the next sequence was running in themicrowave. Work up consisted of partitioning the reaction between ethylacetate and 1N aqueous hydrochloric acid in a 250 ml separatory funnel.The aqueous phase was back extracted once with ethyl acetate and theorganic phases combined and washed sequentially with 1N aqueoushydrochloric acid, 0.1M NaH2PO4, and brine. The solution was thencombined with a previous workup in a 1 L erlenmeyer flask containingmagnesium sulfate. Filter and remove volatiles, dry in vacuuo at roomtemperature overnight to obtain 10.67 g of a yellow-orange foam. Adsorbthe crude product onto 25 g of silica gel using dichloromethane,removing volatiles in vacuuo. Chromatograph on 299 g of silica gelslurry packed in 20% ethyl acetate in hexanes and eluting with 20% ethylacetate in hexanes. Pure product fractions from the chromatography werecombined and solvents removed in vacuuo. The residue was dissolved inbenzene and removed in vacuuo to aid in the removal of trace ethylacetate. The title compound as a yellow foam/amorphous solid was driedin vacuuo overnight at room temperature to yield 6.83 g (71.7%). 1H NMR(500 MHz, CHLOROFORM-D) δ ppm 1.12-1.29 (m, 1H) 1.30-1.61 (m, 4H) 1.64(s, 10H) 1.67-2.00 (m, 4H) 1.98-2.19 (m, 3H) 2.43 (s, 3H) 2.75-2.87 (m,1H) 3.85-4.01 (m, 4H) 5.86 (s, 1H) 7.00 (d, J=2.75 Hz, 1H) 7.11 (dd,J=8.55, 2.75 Hz, 1H) 7.35 (s, 1.8H, benzene) 7.69 (dd, J=8.55, 1.53 Hz,1H) 7.82 (d, J=8.24 Hz, 1H) 8.24 (s, 1H). LC-MS retention time 3.28 min;m/z (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of30% solvent A/70% solvent B to 0% solvent A/100% solvent B, a gradienttime of 5 min, a hold time of 1 min, and an analysis time of 6 min wheresolvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent Bwas 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a Micromass Platform for LC in electrospray mode.

7H-Indolo[2,1-a][2]benzazepine-6-propanoic acid,13-cyclohexyl-10-[(1,1-dimethylethoxy)carbonyl]-3-methoxy-beta-oxo-,ethyl ester

To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,6-acetyl-13-cyclohexyl-3-methoxy-, 1,1-dimethylethyl ester (2.50 g, 5.15mmol) in THF (15.0 mL) was added a 1M solution of LHMDS (5.41 mL, 5.41mmol) in THF at −78° C. and stirred for 15 min. Ethyl cyanoformate(0.510 mL, 5.15 mmol) was added at −78° C. to the resulting solution andstirring continued for 30 min. Saturated aqueous NH₄Cl (50 mL) was addedand the aqueous layer was extracted with CHCl₃ (2×50 mL). The organicphase was dried over Na₂SO₄, filtered, and concentrated under reducedpressure. Silica gel chromatography (2:1 methylene chloride:hexanes) ofthe concentrate afforded the title compound (1.75 g, 61%) as a yellowoil. MS m/z 558 (MH⁺). A previous reaction which was run in an analogousfashion to the above reaction and in which starting material7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,6-acetyl-13-cyclohexyl-3-methoxy-, 1,1-dimethylethyl ester was stillpresent was separated under the following conditions: This proceduredescribes the separation of tert-butyl13-cyclohexyl-6-(3-ethoxy-3-oxopropanoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(desired product) from the starting material ketone, tert-butyl6-acetyl-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate.Total weight of materials was estimated to be 2.6 g. 3.9 g of an thesample mixture as an orange oil was dissolved in dichloromethane andadsorbed on 10 g of silica gel. The volatiles were removed in vacuuousing a rotary evaporator. The sample adsorbed onto silica gel wasapplied to a column of 294 g of silica gel which was slurry packed in30% diethyl ether in hexanes. A bed of sand was placed on top of theadsorbed sample to aid in solvent addition. The approximate size of thesilica gel column packing was 75 mm diameter×175 mm in height. Theproduct was eluted using a gradient of 30% diethyl ether in hexanes to35% diethyl ether in hexanes to 40% diethyl ether in hexanes. Elute withapproximately 1 L of 30% Et2O/hexanes, then 1 L of 35% Et2O/hexanes, andfinally using 40% Et2O/hexanes. The volumes of fractions collected wereapproximately 125 ml to 150 ml. The product fractions were combined andvolatiles removed and the title keto-ester dried in vacuuo to yield 1.63g of a yellow-orange amorphous solid. 1H NMR (500 MHz, CHLOROFORM-D) δppm 1.12 (t, J=7.02 Hz, 2.5H) 1.15-1.28 (m, 1.6H) 1.32 (q, J=7.12 Hz,1.0H) 1.35-1.43 (m, 1.5H) 1.59 (s, 1.5H) 1.61-1.69 (m, 9.4H) 1.72-1.82(m, 2.0H) 1.94 (s, 1.2H) 2.04 (s, 2.9H) 2.76-2.85 (m, 1.0H) 3.64-3.79(m, 0.8H) 3.88 (s, 0.7H) 3.90 (s, 0.7H) 3.92 (s, 2.6H) 3.94-4.06 (m,0.7H) 4.12 (q, J=7.22 Hz, 1.9H) 4.21-4.33 (m, 0.7H) 4.39 (q, J=7.12 Hz,0.2H) 5.67 (s, 0.2H) 5.71-5.90 (m, 0.7H) 6.95-7.02 (m, 1.0H) 7.06 (dd,J=8.55, 2.75 Hz, 0.2H) 7.12 (dd, J=8.70, 2.59 Hz, 0.82H) 7.46-7.57 (m,1.2H) 7.64 (s, 0.8H) 7.69 (d, J=8.55 Hz, 0.9H) 7.76-7.85 (m, 0.9H) 8.14(s, 0.2H) 8.22 (s, 0.8H) 12.40 (s, 0.1H). LC-MS retention time 2.78 min;556 m/z (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 3 min, a hold time of 1 min, and an analysis time of 4 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.

tert-Butyl13-cyclohexyl-6-((2E,Z)-3-(dimethylamino)-2-(ethoxycarbonyl)-2-propenoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate

tert-Butyl13-cyclohexyl-6-(3-ethoxy-3-oxopropanoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(1.63 g, 2.92 mmol) was dissolved in N,N-dimethylformamide dimethylacetal (7.0 mL, 52.7 mmol) in a 50 ml round bottom flask. The reactionwas maintained under a nitrogen atmosphere and heated in oil bath underrefluxing conditions (110° C.) for 2.75 hrs. The reaction was thencooled reaction under a nitrogen atmosphere and the volatiles wereevaporated in vacuuo to give an orange colored foam. TLC analysis (SiO2plate, elution-50% diethyl ether in hexanes) confirmed that the reactionhad gone to completion. This material was dried in vacuuo at roomtemperature overnight to yield 1.87 g of the enamine intermediate as anorange amber foam which was used in the next step without any furtherpurification. LC-MS of intermediate enamine: LC-MS retention time 2.81min; 613 m/z (MH+). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradienttime of 2 min, a hold time of 1 min, and an analysis time of 3 min wheresolvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent Bwas 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determinedusing a Micromass Platform for LC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester and 7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-3-yl]-3-methoxy-,1,1-dimethylethyl ester

The intermediate enamine, tert-butyl13-cyclohexyl-6-((2E,Z)-3-(dimethylamino)-2-(ethoxycarbonyl)-2-propenoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate,(1.83 g, 2.99 mmol) was dissolved in absolute ethanol (10 mL). Within afew minutes of dissolution in ethanol the reaction became heterogeneouswith a fine yellow/orange precipitate forming. Methylhydrazine (0.173mL, 3.29 mmol) was added to the reaction and the reaction was placedunder a nitrogen atmosphere with a condenser. The reaction was heated to80 C and remained heterogeneous at 80 C. An additional 5 ml of absoluteethanol was added and the reaction stirred at 80 C for 15 minutes. Thereaction was still heterogeneous and 1,4-dioxane (5 ml) was added andthe reaction slowly became homogeneous. The reaction was heated for 2hours then cooled and the volatiles removed in vacuuo to obtain anorange amber foam. The residue was dissolved in benzene and thenvolatiles removed in vacuuo and the sample was dried at room temperatureovernight in vacuuo to yield 1.79 g of a yellow amorphous solid/foam.LC-MS analysis indicated two possible isomeric products. 102 mg of thecrude product was purified by reverse phase prep HPLC. The sample waspurified on a Shimadzu high pressure liquid chromatography systememploying Discovery VP software interfaced with a SCL-10A controller,SIL-10A autosampler and FRC-10A fraction collector. The sample wasdissolved in acetonitrile/DMF (1:1) (4 ml) purified using a WatersSunfire Prep C18 OBD, 5 uM 19 mm×100 mm column and monitored using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 25 mL/min, a gradient of 25%solvent A/75% solvent B to 0% solvent A/100% solvent B, a gradient timeof 10 minutes with a run time of 20 minutes using % A=10% acetonitrile,90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA solventsystem. First eluting product is7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester with retention time of 11.7 minutes with theminor component product being7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-3-yl]-3-methoxy-,1,1-dimethylethyl ester with a retention of 14.5 minutes.

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.13-1.27(m, 1H) 1.30 (t, J=7.02 Hz, 3H) 1.34-1.55 (m, 3H) 1.58 (s, 9H) 1.61-1.84(m, 3H) 1.85-2.00 (m, 1H) 1.99-2.18 (m, 3H) 2.86 (t, J=11.75 Hz, 1H)3.28 (s, 3H) 3.90 (s, 3H) 4.27 (d, J=4.27 Hz, 2H) 4.71 (s, 1H) 4.97 (s,1H) 6.77 (s, 1H) 6.93 (d, J=2.44 Hz, 1H) 7.07 (dd, J=8.55, 2.44 Hz, 1H)7.65 (d, J=8.55 Hz, 1H) 7.79-7.88 (m, 2H) 7.97 (s, 1 H). LC-MS retentiontime 3.92 min; 596 m/z (MH+). LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 5 ml/min, a gradientof 70% solvent A/30% solvent B to 0% solvent A/100% solvent B, agradient time of 5 min, a hold time of 1 min, and an analysis time of 6min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetateand solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MSdata was determined using a Micromass Platform for LC in electrospraymode.

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-3-yl]-3-methoxy-,1,1-dimethylethyl ester. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.13-1.26(m, 1H) 1.30 (t, J=7.17 Hz, 3H) 1.33-1.60 (m, 3H) 1.61 (s, 9H) 1.64-1.83(m, 3H) 1.91 (s, 2H) 1.98-2.16 (m, 3H) 2.82-2.91 (m, 1H) 3.90 (s, 3H)3.94 (s, 3H) 4.20-4.30 (m, 2H) 4.41 (d, J=14.04 Hz, 1H) 5.76 (d, J=14.04Hz, 1H) 6.96-7.03 (m, 2H) 7.49-7.54 (m, 1H) 7.64 (dd, J=8.39, 1.37 Hz,1H) 7.79 (d, J=8.55 Hz, 1H) 7.84 (s, 1H) 7.90 (s, 1H) 8.26 (s, 1H).LC-MS retention time 4.26 min; 596 m/z (MH+). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 70% solvent A/30% solvent B to 0% solvent A/100%solvent B, a gradient time of 5 min, a hold time of 1 min, and ananalysis time of 6 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H₂O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. The remainder of the sample (1.615 g) wasadsorbed onto 4 g of silica gel using dichloromethane andchromatographed on 50 g of silica gel slurry packed using 2% ethylacetate in dichloromethane and eluting with 2% ethyl acetate indichloromethane. The first component to elute is the minor product,7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-3-yl]-3-methoxy-,1,1-dimethylethyl ester, 179 mg isolated. The second component,7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester was the major component to elute and yielded 966mg.

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester (53 mg, 0.089 mmol) was dissolved in1,2-dichloroethane (2 mL), under a nitrogen atmosphere. Tifluoroaceticacid was then added (2 ml, 26.0 mmol), and the reaction was stirred atroom temperature for 2.5 hours. The volatiles were then removed invacuuo and the residue dissolved in benzene and the resultant solutionwas evaporated under reduced pressure to remove residual TFA. Thisprocess was repeated once. This gave the title compound as a yellowsolid, (46.2 mg).

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.12-1.26 (m, 1H) 1.31 (t, J=7.02Hz, 3H) 1.40 (s, 2H) 1.51-1.89 (m, 3H) 1.87-2.23 (m, 4H) 2.87 (t,J=11.29 Hz, 1H) 3.29 (s, 3H) 3.91 (s, 3H) 4.27 (br.s, 2H) 4.73 (br.s,1H) 4.97 (br.s, 1H) 6.78 (s, 1H) 6.94 (d, J=2.14 Hz, 1H) 7.08 (dd,J=8.55, 2.44 Hz, 1H) 7.54 (d, J=8.85 Hz, 1H) 7.77 (d, J=8.24 Hz, 1H)7.86-7.95 (m, 2H) 7.98 (s, 1H) 8.36 (br.s, 2H). LC-MS retention time1.84 min; 538 m/z (MH−). LC data was recorded on a Shimadzu LC-10ASliquid chromatograph equipped with a Phenomenex-Luna 10u C18 3.0×50 mmcolumn using a SPD-10AV UV-Vis detector at a detector wave length of 220nM. The elution conditions employed a flow rate of 5 ml/min, a gradientof 70% solvent A/30% solvent B to 0% solvent A/100% solvent B, agradient time of 5 min, a hold time of 0 min, and an analysis time of 5min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetateand solvent B was 5% H₂O/95% acetonitrile/10 mM ammonium acetate. MSdata was determined using a Micromass Platform for LC in electrospraymode.

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-]O-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-,ethyl ester

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-(981mg, 1.818 mmol) was dissolved in THF (18 mL). Carbonyldiimidazole (649mg, 4.00 mmol) was added to the reaction. The reaction was placed undera nitrogen atmosphere and stirred at room temperature for 45 minutesthen heated to reflux for 1 hour. The reaction was cooled under anitrogen atmosphere and propane-2-sulfonamide (1164 mg, 9.45 mmol) wasadded to the reaction followed by DBU (0.548 mL, 3.64 mmol). Thereaction was then immersed in oil bath at 80° C. under nitrogenatmosphere and heated overnight at 70-80° C. The reaction was thendiluted with ethyl acetate and the organic layer washed sequentiallywith 1.0 N aqueous hydrochloric acid, 0.1M aqueous NaH₂PO₄ and brine.The organic layer was dried over MgSO₄, filtered and volatiles removedin vacuuo to yield a yellow foam which was dried in vacuuo at roomtemperature overnight to yield 1.170 g of a yellow amorphous solid.Proton NMR analysis revealed the presence of propane-2-sulfonamide (1.41ppm, d, 500 MHz, CDCl3) in the sample. The crude sample was dissolved inapproximately 200 ml of dichloromethane and washed 2× with 125 ml ofwater, then sequentially with 1N aqueous hydrochloric acid, 2× with 0.1MNaH2PO4 then again with 1N aqueous hydrochloric acid. Thedichloromethane solution was dried over sodium sulfate, filtered andvolatiles removed and the product dried in vacuuo at room temperatureovernight to yield 1.046 g (89%) of the title compound as a yellowamorphous solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.80-0.90 (m, 1H)1.20-1.27 (m, 4H) 1.30 (t, J=7.02 Hz, 4H) 1.32-1.43 (m, 3H) 1.46 (d,J=7.02 Hz, 6H) 1.53-1.64 (m, 3H) 1.79 (d, J=9.77 Hz, 3H) 1.85-2.13 (m,5H) 2.81-2.91 (m, 1H) 3.90 (s, 3H) 4.00-4.10 (m, 1H) 4.24 (s, 2H) 4.71(d, J=12.21 Hz, 1H) 4.99 (d, J=16.48 Hz, 1H) 6.77 (s, 1H) 6.94 (d,J=2.44 Hz, 1H) 7.08 (dd, J=8.55, 2.75 Hz, 1H) 7.38 (dd, J=8.55, 1.22 Hz,1H) 7.52 (d, J=8.85 Hz, 1H) 7.76 (d, J=1.22 Hz, 1H) 7.86-7.92 (m, 2H)8.26 (br.s, 1H). LC-MS retention time 1.79 min; 643 m/z (MH−). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aWaters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, ahold time of 1 min, and an analysis time of 4 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-,ethyl ester (1.044 g, 1.619 mmol) was dissolved in THF (11 ml) withheating. DMF was then added (5 mL) and the mixture was gently heated toensure dissolution. The mixture was then cooled to room temperature andtetrabutylammonium hydroxide (6.5 ml, 6.50 mmol) (1.0M in methanol) wasadded. The resultant mixture was then stirred at room temperature undernitrogen for 2.5 hrs and progress was monidered by LC-MS. Results showedpredominately methyl and ethyl esters. The mixture was then stirred foran additional 3 hrs, after which a further 2.0 mL (2 mmol) oftetrabutylammonium hydroxide (1.0M in methanol) was added and thereaction was stirred at room temperature under nitrogen for a further 2days. Subsequent analysis shows reaction had proceeded to approximately22% conversion to the desired acid product. Volatiles (methanol,ethanol, THF) were removed from the reaction in vacuuo (30° C.) using arotary evaporator. To the reaction was added 200 uL of 10N aqueoussodium hydroxide and 4 ml of THF. The reaction was mixed by placing onrotary evaporator, gently heated (25° C., 3 hrs) then add approximately6 ml of DMF and heat at 35 C for 3 hrs and using house vacuum to removevolatiles generated from hydrolysis. Analysis of the reaction by LC-MSindicated approximately 83% conversion to acid product. The reaction wasstirred overnight at room temperature and subsequent analysis showed noadditional conversion to product. An additional 4.0 ml of 1.0Mtetrabutylammonium hydroxide in methanol was added to the reaction. Thereaction was placed on a rotary evaporator and volatiles removed invacuuo and the reaction continued to heat at 40-45 C for approximately 6hours. The reaction was then worked up by adding 1N aqueous hydrochloricacid (100 ml) into the reaction and then the mixture was rinsed into a500 ml sepratory funnel using ethyl acetate bring the organic volume toapprox. 200 ml. Partition the reaction between ethyl acetate and 1.0Naqueous hydrochloric acid. The organic layer was wash 3× (˜300 ml each)with 1.0N aqueous hydrochloric acid, then brine and dried over MgSO4,filtered and the volatiles removed in vacuuo to yield 1.03 g of a yellowfilm foam. The sample was dried in vacuuo at room temperature to 0.92 g(92%) of the title compound. LC-MS retention time 1.48 min; 615 m/z(MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatographequipped with a Phenomenex-Luna 10u C18 3.0×50 mm column using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 5 ml/min, a gradient of 100%solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient timeof 3 min, a hold time of 1 min, and an analysis time of 4 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray mode.

An alternative procedure for the preparation of the title compound isdescribed below.

Dissolve 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-,ethyl ester (1.044 g, 1.619 mmol) in a pre-mixed solution of THF (20mL), MeOH (20 mL) and sodium hydroxide (20 mL, 20.00 mmol). The reactionwas homogenous and was stirred at room temperature under a nitrogenatmosphere for 26 hrs then concentrated in vacuuo using a rotaryevaporator with a bath temperature at 20 C. The reaction was poured into1N aqueous hydrochloric acid and extract using ethyl acetate. Thecombined organic layers were washed sequentially with 1N aqueoushydrochloric acid and brine, then dried over magnesium sulfate, filteredand solvent removed in vacuuo. The crude product dried in vacuuo at roomtemperature to yield 1.68 g of an orange amorphous solid. The crudeproduct was dissolved in chloroform (approximately 50 mL) with heatingand hexanes were added until some material starts to precipitate butre-dissolves on swirling (approximately 10-12 ml of hexanes). Themixture was allowed to slowly cool to room temperature and then allowedto stand at room temperature for a few hours. The very fine particulateyellow precipitate was filtered using a Buchner funnel and dried invacuuo at room temperature to yield 819 mg (45%) of purified product asa bright yellow amorphous solid. The title compound 4.6 mg was dissolvedin CDCl3 (2 ml) with the addition of approximately 5 drops of CD3OD toaid in dissolution for 1H NMR acquisition. 1H NMR (500 MHz,CHLOROFORM-D/CD3OD) δ ppm 1.11-1.39 (m, 3H) 1.41 (d, J=7.02 Hz, 6H)1.47-1.65 (m, 1H) 1.75 (d, J=8.85 Hz, 2H) 1.82-2.27 (m, 13 H) 2.77-2.90(m, 1H) 3.28 (s, 3H) 3.88 (s, 3H) 3.97-4.06 (m, 1H) 4.66 (s, 1H) 5.01(s, 1H) 6.76 (s, 1H) 6.92 (d, J=2.75 Hz, 1H) 7.04 (dd, J=8.70, 2.59 Hz,1H) 7.47-7.54 (m, 2H) 7.81 (d, J=1.22 Hz, 1H) 7.86 (d, J=8.54 Hz, 1H)7.91 (s, 1H)

LC-MS retention time 1.39 min; 615 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-3-yl]-3-methoxy-

Dissolve 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-3-yl]-3-methoxy-,1,1-dimethylethyl ester (176 mg, 0.295 mmol) in 1,2-dichloroethane (3mL), place reaction under a nitrogen atmosphere, then addtrifluoroacetic acid (3 ml, 38.9 mmol). Stir the reaction at roomtemperature under a nitrogen atmosphere for 2 hr 20 min then removevolatiles in vacuuo. Dissolve product in a mixture of benzene anddichloromethane then remove volatiles in vacuuo. Repeat dissolution inbenzene and dichloromethane and remove volatiles to aid in removal oftrace trifluoroacetic acid. The title compound was dried in vacuuo atroom temperature to yield 164 mg of a yellow amorphous solid. 1H NMR(500 MHz, CHLOROFORM-D) δ ppm 1.01-1.29 (m, 3 H) 1.32 (t, J=7.17 Hz, 3H)1.35-1.53 (m, 2H) 1.52-1.85 (m, 3H) 1.86-2.20 (m, 4 H) 2.79-2.95 (m, 1H)3.91 (s, 3H) 3.97 (s, 3H) 4.27 (q, J=7.22 Hz, 2H) 4.41 (d, J=14.34 Hz,1H) 5.84 (d, J=14.34 Hz, 1H) 6.97-7.08 (m, 2H) 7.54 (d, J=8.24 Hz, 1H)7.76 (d, J=8.55 Hz, 1H) 7.85 (d, J=8.54 Hz, 1H) 7.91 (s, 1H) 7.95 (s,1H) 8.50 (s, 1H). LC-MS retention time 2.08 min; 538 m/z (MH−). LC datawas recorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 70% solvent A/30%solvent B to 0% solvent A/100% solvent B, a gradient time of 5 min, ahold time of 1 min, and an analysis time of 6 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

1H-pyrazole-4-carboxylic acid,3-[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-,ethyl ester

Dissolve 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-3-yl]-3-methoxy-(60mg, 0.111 mmol) in THF (1.0 mL), then add carbonyl diimidazole (42 mg,0.259 mmol) to the reaction. The reaction was stirred under a nitrogenatmosphere for 1 hour at room temperature. The reaction was then heatedat 70 C for 1 hour then cooled and N,N-dimethylsulfamide (70 mg, 0.564mmol) was added to the reaction followed by DBU (0.034 mL, 0.222 mmol).The reaction was again capped under a nitrogen atmosphere and heated at70 C for 16.5 hours. The reaction was diluted with ethyl acetate andwashed sequentially with 1.0N aqueous hydrochloric acid, 0.1M aqueousNaH2PO4 and again with 1.0N aqueous hydrochloric acid, and finally withbrine. The organic phase was dried over magnesium sulfate, filtered,solvent removed and the product dried in vacuuo at room temperature toyield 70 mg of an amorphous yellow solid. 1H NMR (500 MHz, CHLOROFORM-D)δ ppm 0.76-0.95 (m, 2H) 1.12-1.26 (m, 5H) 1.32 (t, J=7.17 Hz, 3H) 1.38(s, 2H) 1.51-1.61 (m, 4H) 1.67-1.81 (m, 3H) 1.87-2.01 (m, 2H) 2.01-2.11(m, 3H) 2.82-2.92 (m, 1H) 3.06 (s, 6 H) 3.91 (s, 3H) 3.96 (s, 3H) 4.26(d, J=7.02 Hz, 2H) 4.42 (d, J=14.34 Hz, 1H) 5.75 (d, J=14.04 Hz, 1H)6.99-7.05 (m, 2H) 7.38 (d, J=8.24 Hz, 1H) 7.52 (d, J=8.24 Hz, 1H) 7.85(d, J=8.55 Hz, 1H) 7.89-7.96 (m, 2H) 8.18 (s, 1H) 8.36 (br.s, 1H). LC-MSretention time 2.34 min; 644 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

1H-pyrazole-4-carboxylic acid,3-[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-

1H-pyrazole-4-carboxylic acid,3-[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-,ethyl ester (66 mg, 0.102 mmol) was dissolved in THF (1 mL) and a 1.0Msolution of tetrabutylammonium hydroxide (0.41 mL, 0.410 mmol) inmethanol was added to the reaction. The reaction was stirred at roomtemperature under a nitrogen atmosphere for 4 hrs then analyzed byLC-MS. The reaction was concentrated in vacuuo on a rotary evaporatorthen 1 ml of THF was added to the reaction and the reaction once againcapped under a nitrogen atmosphere. The reaction was placed in a waterbath at 40 C and allowed to stir overnight. Sometime overnight theheating element on the water bath failed and the reaction was observedto at room temperature the next morning. LC-MS analysis of the reactionindicated the reaction was complete. The reaction was diluted with ethylacetate and washed sequentially with 1.0N aqueous hydrochloric acid,then again with 1.0N aqueous hydrochloric acid and finally with brine.The organic layer was dried over magnesium sulfate, filtered and solventremoved in vacuuo. The title compound was dried in vacuuo to yield 63 mgof an amorphous yellow solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm0.81-0.97 (m, 3H) 1.18-1.30 (m, 4 H) 1.30-1.65 (m, 6H) 1.66-1.83 (m, 3H)1.84-2.10 (m, 6H) 2.84-2.92 (m, 3H) 3.04 (s, 6H) 3.88 (s, 3H) 3.97 (s,3H) 4.43 (d, J=14.34 Hz, 1H) 5.68 (d, J=13.73 Hz, 1H) 6.99 (d, J=2.75Hz, 1H) 7.02 (dd, J=8.55, 2.44 Hz, 1H) 7.35 (d, J=8.24 Hz, 1H) 7.52 (d,J=8.55 Hz, 1H) 7.77 (s, 1H) 7.83 (d, J=8.24 Hz, 1H) 7.98 (s, 1H) 8.15(s, 1H) 8.71 (s, 1H). LC-MS retention time 1.58 min; 616 m/z (MH−). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Phenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, ahold time of 1 min, and an analysis time of 4 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-3-yl]-

1H-pyrazole-4-carboxylic acid,3-[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(57mg, 0.092 mmol) was dissolved in DMF (1.0 ml) and TBTU (55.8 mg, 0.174mmol) added to the reaction. The reaction was capped under a nitrogenatmosphere and stir at room temperature for 1 hour then DMAP (47 mg,0.385 mmol) was added to the reaction followed by morpholine (16 μL,0.184 mmol). The reaction was capped under a nitrogen atmosphere andstirred at room temperature overnight. The reaction was diluted withethyl acetate and washed sequentially with 1.0N aqueous hydrochloricacid, 0.1M aqueous NaH2PO4 and brine. The organic phase was dried overmagnesium sulfate, filtered and solvent removed in vacuuo. The titlecompound was dried overnight in vacuuo at room temperature to yield 63mg of a yellow amorphous solid. The title compound was further purifiedon a Shimadzu high pressure liquid chromatography system employingDiscovery VP software interfaced with a SCL-10A controller, SIL-10Aautosampler and FRC-10A fraction collector. The sample was dissolved inacetonitrile/DMF (1:1) (total volume 2 ml) purified using a WatersSunfire Prep C18 OBD, 5 uM 19 mm×100 mm column and monitored using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 25 mL/min, a gradient of 60%solvent A/40% solvent B to 0% solvent A/100% solvent B, a gradient timeof 12 minutes with a run time of 25 minutes using % A=10% acetonitrile,90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA solventsystem. The sample was run as two 1 ml injections. The run time of thesecond Prep HPLC run was truncated to 15 minutes base on data from thefirst run. The product fractions (retention time=8.75 min.) werecombined and solvent removed in vacuuo. The compound was dried at roomtemperature in vacuuo to yield 38 mg of the title compound as a yellowamorphous solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.23 (q, J=12.21Hz, 1H) 1.30-1.56 (m, 3H) 1.77 (d, J=10.38 Hz, 2H) 1.90-2.14 (m, 4H)2.54-2.81 (m, 4H) 2.82-2.95 (m, 2 H) 2.95-3.05 (m, 2H) 3.07 (s, 6H)3.09-3.39 (m, 5H) 3.90 (s, 3H) 3.97 (s, 3H) 4.45 (d, J=14.65 Hz, 1H)5.45 (d, J=14.65 Hz, 1H) 6.95 (d, J=2.75 Hz, 1H) 6.97 (s, 1H) 7.04 (dd,J=8.70, 2.59 Hz, 1H) 7.46 (dd, J=8.55, 1.53 Hz, 1H) 7.52 (d, J=8.55 Hz,1H) 7.55 (s, 1H) 7.89 (d, J=8.55 Hz, 1H) 7.94 (d, J=1.22 Hz, 1H) 9.13(br.s, 1 H). LC-MS retention time 1.82 min; 685 m/z (MH−). LC data wasrecorded on a Shimadzu LC-10AS liquid chromatograph equipped with aPhenomenex-Luna 10u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, ahold time of 1 min, and an analysis time of 4 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[[4-(1-methylethyl)-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(0.92g, 1.5 mmol) was dissolved in DMF (25 ml) and HATU (1141 mg, 3.0 mmol)was added followed by diisopropylethylamine (1306 uL, 7.5 mmol). A 1 mLsolution of the reaction solution containing 1H-pyrazole-4-carboxylicacid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-/HATU/DIEAwas transferred a 16×100 mm wheaton vial containing1-isopropylpiperazine (36.9 mg, 0.288 mmol). The reaction was capped andshaken at room temperature overnight. The reaction was transferred intoa 96 well plate and the reaction vial rinsed with DMF (800 uL) to bringthe final reaction volume to 1.800 mL. The reaction mixture was purifiedby reverse phase HPLC under the following conditions. The Prep HPLC wascontrolled by Dionex Chromeleon 6.70 sp1 LC software using Varian aprostar binary pump with 50 mL/min pump head and detection using a Sedex75 ELS detector for fraction collection. A Dionex UVD340U UVspectrometer was used to observe the UV trace of the HPLC run. A WatersSunfire C18 19 mm×25 mm 10u was employed for the isolation using asolvent system of A=water and 20 mM ammonium acetate, B=acetonitrile.The following gradient was used: 80% A and 20% B hold for 3 minutesfollowed by a 19 minute gradient to 5% A and 95% B with a final hold at5% A and 95% B of 5 minutes. The flow rate for purification was 20ml/min. The fractions of interest were collected and concentrated todryness using a Zymark Turbo Vap Evaporator. NMR analysis was performedon the peaks of interest (analytical retention time 5.69 minutes and6.30 minutes). The title compound was determined to be the peak withanalytical retention time of 6.30 minutes by NMR analysis (rotomers). 1HNMR (500 MHz, CHLOROFORM-D) δ ppm 0.17 (s, 0.5H) 0.91 (t, J=6.87 Hz,3.3H) 1.10 (t, J=14.95 Hz, 1.2H) 1.17-1.32 (m, 2.6H) 1.33-1.59 (m,13.1H) 1.68-1.83 (m, 3.5H) 1.88-2.18 (m, 8.7H) 2.20-2.67 (m, 7.8H)2.76-3.05 (m, 3.3H) 3.23 (d, J=10.99 Hz, 1.3H) 3.29-3.53 (m, 1.6H)3.63-3.86 (m, 2.7H) 3.88-3.98 (m, 6.0H) 4.02-4.10 (m, 1.0H) 4.61 (d,J=14.65 Hz, 1.3H) 4.89 (d, J=14.95 Hz, 0.9H) 6.76-6.86 (m, 0.8H)6.91-7.00 (m, 1.9H) 7.06-7.13 (m, 1.3H) 7.51-7.57 (m, 1.4H) 7.57-7.66(m, 1.6H) 7.66-7.75 (m, 1.9H) 7.89 (d, J=8.55 Hz, 1.5H). LCMS analysisusing MassLynx 4.0 SP4 LC-MS software, a CTC-Leap HTS-PAL autosampler,with an Agilent 1100 binary pump, Agilent 1100 photodiode array UVdetector, Polymer Lab 2100 ELS detector (Temp=45 C, nebulizer temp 35 C)and a Waters ZQ With ESCi mass spectrometer. The analysis was performedusing a Phenomenex Gemini 4.6×150 mm C18 3u column with a mobile phasesolvent system of A=water and 20 mM ammonium acetate, B=acetonitrilewith a flow rate of 1.0 ml/min and a gradient starting at 70% A and 30%B and a final composition 5% A and 95% B, gradient time of 11 minutesand a hold time of 2 minutes to give an analysis runtime of 13 minutes.

Retention time=6.63 minutes, m/z=725 (MH+).

The following compounds were synthesized by an analogous method asdescribed above for 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-3-yl]-and 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[[4-(1-methylethyl)-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-.Analytical LCMS data on the following examples were acquired using thefollowing columns and conditions. Method 1: Gradient: 3 minutes; Flowrate: 5 mL/min; Stop time: Gradient time+1 minute; Eluent A: 5%CH₃CN/95% H₂O with 10 mM NH₄OAc; Eluent B: 95% CH₃CN/5% H₂O with 10 mMNH₄OAc; Initial % B=30; Final % B=100; Column: Waters Xterra, 3 mm×50mm, S7. Method 2: Gradient: 3 minutes; Flow rate: 5 mL/min; Stop time:Gradient time+1 minute; Eluent A=10% methanol, 90% water, 0.1%trifluoroacetic acid; % B=90% methanol, 10% water, 0.1% trifluoroaceticacid; Initial % B=40; Final % B=100; Column: Phenomenex Luna 3.0 mm×50mm S10.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[methyl(1-methyl-3-pyrrolidinyl)amino]carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-

LCMS: m/e 756 (M+H), ret time 2.30 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-

LCMS: m/e 756 (M+H), ret time 2.10 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[3-(dimethylamino)-1-pyrrolidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-

LCMS: m/e 756 (M+H), ret time 2.40 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-

LCMS: m/e 729 (M+H), ret time 2.60 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[2-[(dimethylamino)methyl]-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-

LCMS: m/e 787 (M+H), ret time 2.40 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-

LCMS: m/e 757 (M+H), ret time 2.80 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-

LCMS: m/e 768 (M+H), ret time 2.40 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-

LCMS: m/e 768 (M+H), ret time 2.10 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1R,4R)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-

LCMS: m/e 768 (M+H), ret time 2.30 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,6-[4-(7-azabicyclo[2.2.1]hept-7-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-13-cyclohexyl-3-methoxy-N-(4-morpholinylsulfonyl)-

LCMS: m/e 739 (M+H), ret time 3.10 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[(4-methyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-

LCMS: m/e 742 (M+H), ret time 2.30 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[4-(1-methylethyl)-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-

LCMS: m/e 771 (M+H), ret time 2.40 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[3-(dimethylamino)-1-piperidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-

LCMS: m/e 771 (M+H), ret time 2.20 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[(1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-

LCMS: m/e 768 (M+H), ret time 2.60 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[(1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl]carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-

LCMS: m/e 768 (M+H), ret time 2.60 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[(1-oxo-2,7-diazaspiro[4.5]dec-7-yl)carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-

LCMS: m/e 797 (M+H), ret time 2.40 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[2-(1-piperidinylmethyl)-1-pyrrolidinyl]carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-

LCMS: m/e 811 (M+H), ret time 2.50 min.

1-piperazinecarboxylic acid,4-[[5-[13-cyclohexyl-3-methoxy-10-[[(4-morpholinylsulfonyl)amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-1H-pyrazol-4-yl]carbonyl]-,ethyl ester.

LCMS: m/e 800 (M+H), ret time 2.60 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2-methoxyethyl)(1-methylethyl)amino]carbonyl]-1-methyl-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-

LCMS: m/e 759 (M+H), ret time 2.80 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[[2-(dimethylamino)ethyl]methylamino]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-

LCMS: m/e 744 (M+H), ret time 2.20 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[4-(1-pyrrolidinyl)-1-piperidinyl]carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-

LCMS: m/e 797 (M+H), ret time 2.30 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-

LCMS: m/e 773 (M+H), ret time 2.60 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(3-endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-

LCMS: m/e 784 (M+H), ret time 2.70 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-

LCMS: m/e 771 (M+H), ret time 2.30 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-

LCMS: m/e 771 (M+H), ret time 2.60 min.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-

LCMS: m/e 686 (M+H), ret time 3.49 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

LCMS: m/e 725 (M+H), ret time 2.99 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

LCMS: m/e 725 (M+H), ret time 3.11 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,6-[4-(7-azabicyclo[2.2.1]hept-7-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-

LCMS: m/e 696 (M+H), ret time 3.32 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[(4-methyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-

LCMS: m/e 699 (M+H), ret time 3.05 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[[4-(1-methylethyl)-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-

LCMS: m/e 727 (M+H), ret time 3.19 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2-methoxyethyl)(1-methylethyl)amino]carbonyl]-1-methyl-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-

LCMS: m/e 716 (M+H), ret time 3.37 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[[4-(1-pyrrolidinyl)-1-piperidinyl]carbonyl]-1H-pyrazol-5-yl]-

LCMS: m/e 753 (M+H), ret time 3.22 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-

LCMS: m/e 730 (M+H), ret time 3.51 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(3-endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

LCMS: m/e 740 (M+H), ret time 2.53 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-

LCMS: m/e 727 (M+H), ret time 2.26 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

LCMS: m/e 727 (M+H), ret time 3.50 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-

LCMS: m/e 712 (M+H), ret time 2.65 min (method 1).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-

LCMS: m/e 740 (M+H), ret time 2.84 min (method 1).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-

LCMS: m/e 756 (M+H), ret time 2.79 min (method 1).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-6-[4-[[3-(dimethylamino)-1-piperidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-

LCMS: m/e 753 (M+H), ret time 2.41 min (method 1).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-6-[4-[[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-

LCMS: m/e 751 (M+H), ret time 2.51 min (method 1).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-6-[4-[(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-

LCMS: m/e 751 (M+H), ret time 2.29 min (method 1).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-6-[4-[[ethyl(1-methylethyl)amino]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-

LCMS: m/e 712 (M+H), ret time 2.45 min (method 1).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-

LCMS: m/e 751 (M+H), ret time 2.36 min (method 1).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-3-methoxy-6-[1-methyl-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-

LCMS: m/e 753 (M+H), ret time 2.39 min (method 1).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-

LCMS: m/e 754 (M+H), ret time 2.87 min (method 1).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-3-methoxy-6-[1-methyl-4-(3-oxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1H-pyrazol-5-yl]-

LCMS: m/e 752 (M+H), ret time 2.92 min (method 1).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(30mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA(0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred atRT for 15 min. 3-methyl-3,8-diazabicyclo[3.2.1]octane, 2HCl (14.21 mg,0.071 mmol) was then added and the solution was stirred at RT overnight.The reaction mixture was then purified by preparative HPLC usingCH₃CN—H₂O-TFA as solvent system. Homogeneous fractions were combined andconcentrated to afford the title compound as a brown colored solid,(36.3 mg, 0.043 mmol, 89% yield).

MS m/z 739 (MH⁺), Retention time: 2.070 min. (basic)

1H NMR (500 MHz, MeOD) δ ppm 1.12 (d, J=6.71 Hz, 6H) 1.18-2.19 (m, 14H)2.24-2.37 (m, 1H) 2.75 (s, 3H) 2.81-3.28 (m, 7H) 3.45-3.52 (m, 2H)3.63-3.83 (s, br, 3H) 3.91 (s, 3H) 4.61 (d, J=14.65 Hz, 1H) 4.90-4.94(m, 1H) 7.07-7.19 (m, 3H) 7.54-7.60 (m, 2H) 7.81 (s, br, 2H) 7.93 (d,J=8.54 Hz, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-(3-oxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(30mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA(0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred atRT for 15 min. 3-oxa-9-azabicyclo[3.3.1]nonane, HCl (11.67 mg, 0.071mmol) was then added and the solution was stirred at RT overnight. Thereaction mixture was then purified by preparative HPLC usingCH₃CN—H₂O-TFA as solvent system. Homogeneous fractions were combined andconcentrated under vacuum. The title compound was obtained as a brownishsolid, (29.5 mg, 0.040 mmol, 84% yield).

MS m/z 738 (M−H⁻), Retention time: 1.928 min. (basic)

1H NMR (500 MHz, MeOD) δ ppm 1.04-2.40 (m, 23H) 2.72-3.05 (m, 3 H)3.41-4.02 (m, 12H) 4.61-4.69 (m, br, 1H) 4.99-5.08 (m, br, 1H) 7.09-7.25(m, 3H) 7.55-7.66 (m, 2H) 7.66-7.73 (m, 1H) 7.85-8.03 (m, 2H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(30mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA(0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred atRT for 15 min. Octahydropyrrolo[1,2-a]pyrazine (9.00 mg, 0.071 mmol) wasthen added and the solution was stirred at RT overnight. The reactionmixture was then purified by preparative HPLC column using CH₃CN—H₂O-TFAas solvent system. Homogeneous fractions were combined and concentratedunder speed vacuum. The TFA salt of the title compound was obtained as abrownish solid, (35.5 mg, 0.042 mmol, 88% yield).

MS m/z 737 (M−H⁻), Retention time: 1.722 min. (basic)

1H NMR (500 MHz, MeOD) δ ppm 1.15 (d, J=6.71 Hz, 6H) 1.19-2.23 (m, 14H)2.26-2.40 (m, 1H) 2.88-3.05 (m, 1H) 3.11-3.58 (m, 11H) 3.72 (s, 3H) 3.95(s, 3H) 4.60-4.70 (m, br, 1H) 5.00-5.16 (m, br, 1H) 7.11 (s, 1H) 7.16(d, J=2.44 Hz, 1H) 7.20 (dd, J=8.54, 2.75 Hz, 1H) 7.58-7.64 (m, 2H) 7.76(s, 1H) 7.91 (s, 1H) 7.99 (d, J=8.55 Hz, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(2-methylpropyl)sulfonyl]-6-[1-methyl-4-[[cis-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(30mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA(0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred atRT for 15 min. Cis-1,2,6-trimethylpiperazine (9.15 mg, 0.071 mmol) wasthen added and the solution was stirred at RT overnight. The reactionmixture was then purified by preparative HPLC using CH₃CN—H₂O-TFA assolvent system. Homogeneous fractions were combined and concentratedunder vacuum. The TFA salt of the title compound was obtained as abrownish solid, (39.1 mg, 0.046 mmol, 96% yield).

MS m/z 739 (M−H⁻), Retention time: 1.723 min. (basic)

1H NMR (500 MHz, MeOD) δ ppm 1.15 (d, J=7.02 Hz, 6H) 1.21-1.65 (m, 10H)1.77-2.22 (m, 6H) 2.28-2.40 (m, 1H) 2.54-3.05 (m, 8H) 3.51 (d, J=6.41Hz, 2H) 3.74 (s, 3H) 3.95 (s, 3H) 4.03-4.42 (m, br, 2H) 4.59-4.70 (m,br, 1H) 5.01-5.12 (m, br, 1H) 7.13 (s, 1H) 7.16 (d, J=2.75 Hz, 1H) 7.21(dd, J=8.85, 2.75 Hz, 1H) 7.59-7.66 (m, 2H) 7.74 (s, 1H) 7.93 (s, 1H)8.00 (d, J=8.55 Hz, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(30mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA(0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred atRT for 15 min. (1S,4S)-2-ethyl-2,5-diazabicyclo[2.2.1]heptane, 2TFA(25.3 mg, 0.071 mmol) was then added and the resultant solution wasstirred at RT for 3 hours. LC/MS analysis showed that the reaction hadprogressed to completion. The reaction mixture was then purified bypreparative HPLC using CH₃CN—H₂O-TFA as solvent system. Homogeneousfractions were collected and concentrated under vacuum. The TFA of thetitle compound was obtained as a brown colored solid, (35.30 mg, 0.041mmol, 87% yield).

MS m/z 737 (M−H⁻), Retention time: 1.850 min. (basic)

1H NMR (500 MHz, MeOD) δ ppm 1.15 (d, J=6.71 Hz, 6H) 1.21-2.22 (m, 15H)2.25-2.39 (m, 1H) 2.89-3.02 (m, 1H) 3.05-3.80 (m, 12H) 3.95 (s, 3H)4.09-4.48 (m, 1H) 4.57-4.70 (m, 1H) 4.99-5.12 (m, 1H) 6.97-7.08 (s, br,1H) 7.14 (s, 1H) 7.20 (dd, J=8.55, 2.44 Hz, 1H) 7.61 (d, J=8.85 Hz, 2H)7.82 (s, 1H) 7.88 (s, 1H) 7.97 (d, J=8.55 Hz, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(30mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA(0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred atRT for 15 min. Morpholine (6.22 mg, 0.071 mmol) was then added and theresultant solution was stirred at RT for 3 hours. LC/MS analysis showedthe reaction had progressed to completion. The reaction mixture was thenpurified by preparative HPLC using CH₃CN—H₂O-TFA as solvent system.Homogeneous fractions were combined and concentrated under vacuum. Thetitle compound was obtained as a yellow solid, (28.4 mg, 0.041 mmol, 85%yield).

MS m/z 698 (M−H⁻), Retention time: 1.618 min. (basic)

1H NMR (500 MHz, MeOD) δ ppm 1.16 (d, J=6.71 Hz, 6H) 1.21-1.36 (m, 1H)1.40-1.64 (m, 3H) 1.75-1.87 (m, 2H) 1.94-2.25 (m, 4H) 2.27-2.41 (m, 1H)2.70-3.12 (m, 9H) 3.49-3.55 (m, 2H) 3.85 (s, 3H) 3.95 (s, 3H) 4.69 (d,J=14.34 Hz, 1H) 5.10 (d, J=14.95 Hz, 1H) 7.09 (s, 1H) 7.16 (d, J=2.44Hz, 1H) 7.20 (dd, J=8.55, 2.44 Hz, 1H) 7.62 (d, J=8.54 Hz, 2H) 7.66 (s,1H) 7.94 (s, 1H) 7.99 (d, J=8.55 Hz, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[cis-2,6-dimethyl-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(30mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA(0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred atRT for 15 min. Cis-2,6-dimethylmorpholine (8.22 mg, 0.071 mmol) was thenadded and the resultant solution was stirred at RT for 3 hours. LC/MSthen showed that the reaction had progressed to completion. The reactionmixture was then purified by preparative HPLC using CH₃CN—H₂O-TFA assolvent system. Homogeneous fractions were collected and concentratedunder vacuum. The title compound was obtained as a yellow colored solid,(29.6 mg, 0.041 mmol, 85% yield).

MS m/z 726 (M−H⁻), Retention time: 1.753 min. (basic)

1H NMR (500 MHz, MeOD) δ ppm 0.50-2.56 (m, 23H) 2.68-3.06 (m, 2 H)3.21-3.63 (m, 7H) 3.83-4.02 (m, 6H) 4.67 (d, J=14.34 Hz, 1H) 5.04 (d,J=14.65 Hz, 1H) 7.11-7.25 (m, 3H) 7.56-7.69 (m, 3H) 7.93 (s, 1H) 7.99(d, J=8.24 Hz, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(30mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA(0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred atRT for 15 min. (S)-2-(methoxymethyl)morpholine, HCl (11.96 mg, 0.071mmol) was then added and the resultant solution was stirred at RT for 3hours. LC/MS analysis then showed the reaction had progressed tocompletion. The reaction mixture was then purified by preparative HPLCusing CH₃CN—H₂O-TFA as solvent system. Homogeneous fractions werecombined and concentrated under vacuum. The title compound was obtainedas a yellow colored solid, (28.6 mg, 0.038 mmol, 81% yield).

MS m/z 742 (M−H⁻), Retention time: 1.598 min. (basic)

1H NMR (500 MHz, MeOD) δ ppm 1.16 (d, J=6.71 Hz, 6H) 1.22-1.65 (m, 4H)1.75-2.24 (m, 6H) 2.28-2.42 (m, 1H) 2.88-3.63 (m, 15H) 3.81 (s, 3H) 3.95(s, 3H) 4.61-4.72 (m, 1H) 5.02-5.14 (m, 1H) 7.11 (s, 1H) 7.17 (d, J=2.44Hz, 1H) 7.20 (dd, J=8.55, 2.44 Hz, 1H) 7.56-7.65 (m, 2H) 7.66 (s, 1H)7.93 (s, 1 H) 7.96-8.03 (m, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[3-(dimethylamino)-1-piperidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(30mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA(0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred atRT for 15 min. N,N-dimethylpiperidin-3-amine, 2HCl (14.35 mg, 0.071mmol) was then added and the resultant solution was stirred at RT for 3hours. LC/MS then showed the reaction had progressed to completion. Thereaction mixture was then purified by preparative HPLC usingCH₃CN—H₂O-TFA as solvent system. Homogeneous fractions were collectedand concentrated under vacuum. The TFA salt of the title compound wasobtained as a yellow colored solid, (36.3 mg, 0.042 mmol, 89% yield).

MS m/z 739 (M−H⁻), Retention time: 1.810 min. (basic)

1H NMR (500 MHz, MeOD) δ ppm 1.16 (d, J=6.71 Hz, 6H) 1.22-1.64 (m, 6H)1.75-2.24 (m, 8H) 2.29-2.39 (m, 1H) 2.46-3.13 (m, 11H) 3.51 (d, J=6.41Hz, 2H) 3.83 (s, 3H) 3.95 (s, 3H) 4.16 (s, br, 1H) 4.61-4.73 (m, br, 1H)5.00-5.12 (m, br, 1H) 7.09 (s, 1H) 7.16 (d, J=2.44 Hz, 1H) 7.20 (dd,J=8.70, 2.59 Hz, 1H) 7.60 (d, J=8.85 Hz, 1H) 7.64 (dd, J=8.55, 1.22 Hz,1H) 7.69 (s, 1H) 7.94 (s, 1H) 8.01 (d, J=8.24 Hz, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(30mg, 0.048 mmol) in DMSO (1 mL), TBTU (22.91 mg, 0.071 mmol) and DIPEA(0.042 mL, 0.238 mmol) were added. The reaction mixture was stirred atRT for 15 min. 3,7-dioxa-9-azabicyclo[3.3.1]nonane (9.21 mg, 0.071 mmol)was then added and the solution was stirred at RT overnight. LC/MS thenshowed that only 40% SM had reacted. Two more equivalents of TBTU werethen added and the reaction mixture was stirred at RT overnight. LC/MSthen showed that the reaction had progressed to completion. The reactionmixture was then purified by preparative HPLC using CH₃CN—H₂O-TFA assolvent system. Homogeneous fractions were combined and evaporated undervacuum to give the title compound as a light-yellow colored solid, (26.7mg, 0.036 mmol, 76% yield).

MS m/z 740 (M−H⁻), Retention time: 1.887 min. (basic)

1H NMR (500 MHz, MeOD) δ ppm 1.16 (d, J=6.71 Hz, 6H) 1.21-1.64 (m, 4H)1.71-3.15 (m, 10H) 3.43-3.88 (m, 13H) 3.96 (s, 3H) 4.63-4.72 (m, 1H)5.01-5.11 (m, 1H) 7.13-7.18 (m, 2H) 7.22 (dd, J=8.70, 2.59 Hz, 1H) 7.61(d, J=8.55 Hz, 1H) 7.64 (d, J=8.85 Hz, 1H) 7.74 (s, 1H) 7.91 (s, 1H)7.98 (d, J=8.55 Hz, 1H).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl)-,ethyl ester

CDI (451 mg, 2.78 mmol) was added to a THF (10 mL) solution of7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-(750mg, 1.39 mmol) and the resultant mixture was stirred at 60° C. for 1 h.The reaction was then cooled to r.t. and butane-2-sulfonamide (572 mg,4.17 mmol) and DBU (0.419 mL, 2.78 mmol) were added. The mixture wasthen heated at 60° C. overnight, after which the solvent was removed andthe residue dissolved in EtOAc. The organic layer was washed withsequentially with 1N HCl solution (3×20 mL), and Brine (3×20 mL) andthen dried over Na₂SO₄. The mixture was then filtered and the filtratewas evaporated in vacuo. The residue was purified using a Shimadzupreparative HPLC employing ACN/water and 0.1% TFA buffer with a Xterracolumn, 30 mm×100 mm, Gradient over 15 min; Starting conc: 10% B; Endingconc: 100% B. Homogeneous fractions were combined and evaporated underreduced pressure to afford the title compound as light yellow solid,(450 mg, 49%). ESI-MS m/e 659 (MH⁺).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-

NaOH (1N, 5 mL) was added to a solution of 1H-pyrazole-4-carboxylicacid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-,ethyl ester (250 mg, 0.379 mmol) in a 1:1 mixture of THF:MeOH (10 mL)and the resultant solution was agitated at r.t. for 48 h. HCl (1N, 5 mL)was then added and the resultant mixture was evaporated under reducedpressure. The residue was dissolved in EtOAc and washed with brine (3×20mL) and then dried over Na₂SO₄. The mixture was then filtered and thefiltrate was evaporated in vacuo to afford the title product as yellowsolid, (235 mg, 98%). ESI-MS m/e 631 (MH⁺).

Using the standard amide coupling conditions described for relatedexamples, the following examples can be prepared.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-N-[(1-methylpropyl)sulfonyl]-

ESI-MS m/e 739 (MH⁺). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.08 (t,J=7.32 Hz, 3H) 1.16-1.56 (m, 9H) 1.58-1.85 (m, 4H) 1.90-2.24 (m, 6H)2.48-2.62 (m, 3H) 2.81-2.99 (m, 3H) 3.15-3.45 (m, 3H) 3.73-4.05 (m, 5H)3.94 (s, 3H) 4.58-4.69 (m, 1H) 4.80-5.02 (m, 1H) 6.92-7.01 (m, 2H) 7.13(dd, J=8.70, 2.29 Hz, 1H) 7.53-7.82 (m, 4H) 7.92 (d, J=8.24 Hz, 1H)10.14 (s, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-(3-oxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1H-pyrazol-5-yl]-N-[(1-methylpropyl)sulfonyl]-

ESI-MS m/e 740 (MH⁺). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.00-1.57 (m,12H) 1.68-1.84 (m, 3H) 1.91-2.48 (m, 9H) 2.81-2.94 (m, 1H) 3.03-3.16 (m,1H) 3.18-3.72 (m, 5H) 3.76-4.02 (m, 7H) 4.53-4.68 (m, 1H) 4.94 (d,J=15.87 Hz, 1H) 6.81-6.91 (m, 1H) 6.94 (d, J=2.44 Hz, 1H) 7.13 (d,J=8.54 Hz, 1H) 7.54-7.62 (m, 1H) 7.62-7.85 (m, 3H) 7.87-7.96 (m, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylpropyl)sulfonyl]-

ESI-MS m/e 742 (MH⁺). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.02-1.13 (m,3H) 1.15-1.27 (m, 1H) 1.31-1.56 (m, 6H) 1.69-1.84 (m, 2H) 1.92-2.39 (m,6H) 2.62-2.70 (m, 1H) 2.83-2.93 (m, 1H) 3.25 (s, 1H) 3.30-3.49 (m, 3H)3.52-3.59 (m, 1H) 3.66-3.76 (m, 3H) 3.80-3.86 (m, 2H) 3.89 (s, 3H) 3.94(s, 3H) 4.63 (d, J=15.26 Hz, 1H) 4.93 (d, J=15.56 Hz, 1H) 6.86 (s, 1H)6.95 (d, J=2.44 Hz, 1H) 7.13 (dd, J=8.70, 2.59 Hz, 1H) 7.59 (d, J=8.55Hz, 1H) 7.63 (d, J=8.54 Hz, 1H) 7.72 (d, J=5.49 Hz, 2H) 7.94 (d, J=8.55Hz, 1H) 10.08-10.26 (m, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylpropyl)sulfonyl]-

ESI-MS m/e 739 (MH⁺). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.85-1.56 (m,15H) 1.58-2.39 (m, 8H) 2.68-2.96 (m, 4H) 3.03-3.38 (m, 3H) 3.55 (d,J=5.19 Hz, 1H) 3.72-4.03 (m, 5H) 4.05-4.43 (m, 2H) 4.51-5.04 (m, 3 H)6.68-6.86 (m, 1H) 6.88-7.18 (m, 2H) 7.49-7.97 (m, 5H) 8.17-8.28 (m, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylpropyl)sulfonyl]-

ESI-MS m/e 739 (MH⁺) 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.00-1.13 (m,3H) 1.21-1.58 (m, 7H) 1.59-1.85 (m, 4H) 1.90-2.49 (m, 11H) 2.80-2.99 (m,2H) 3.34-3.88 (m, 9H) 3.92 (s, 3H) 4.54-4.69 (m, 1H) 4.76-5.00 (m, 1H)6.83-6.94 (m, 1H) 6.97 (s, 1H) 7.06-7.15 (m, 1H) 7.48-7.68 (m, J=35.71Hz, 3H) 7.75 (s, 1H) 7.89 (s, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-N-[(1-methylpropyl)sulfonyl]-

ESI-MS m/e 700 (MH⁺) 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.02-1.14 (m,3H) 1.16-1.30 (m, 1H) 1.49 (dd, J=20.91, 6.87 Hz, 6H) 1.34-1.45 (m, 1H)1.93-2.40 (m, 7H) 2.58-2.71 (m, 1H) 2.77-2.97 (m, 4H) 3.04-3.25 (m, 2 H)3.35-3.65 (m, 2H) 3.79-3.88 (m, 1H) 3.90 (s, 3H) 3.94 (s, 3H) 4.61 (d,J=15.87 Hz, 1H) 4.90 (d, J=15.56 Hz, 1H) 6.86 (s, 1H) 6.96 (d, J=2.44Hz, 1H) 7.13 (dd, J=8.55, 2.44 Hz, 1H) 7.58 (d, J=8.55 Hz, 1H) 7.61 (d,J=7.93 Hz, 1H) 7.65-7.74 (m, 2H) 7.94 (d, J=8.54 Hz, 1H) 10.20-10.44 (m,1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylpropyl)sulfonyl]-

ESI-MS m/e 728 (MH⁺) 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.98-1.13 (m,3H) 1.14-1.31 (m, 2H) 1.34-1.59 (m, 6H) 1.70-1.86 (m, 3H) 1.88-2.32 (m,12H) 2.81-2.98 (m, 1H) 2.95-3.14 (m, 1H) 3.13-3.34 (m, 2H) 3.36-3.67 (m,1H) 3.83-3.93 (m, 1H) 3.92 (s, 3H) 3.95 (s, 3H) 4.61 (d, J=14.34 Hz, 1H)4.91 (d, J=15.56 Hz, 1H) 6.83 (s, 1H) 6.96 (s, 1H) 7.13 (d, J=8.55 Hz,1H) 7.51-7.81 (m, 4H) 7.92 (d, J=7.32 Hz, 1H) 10.33-10.59 (m, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylpropyl)sulfonyl]-6-[1-methyl-4-[(3,4,5-trimethyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-

ESI-MS m/e 741 (MH⁺). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.85-2.25 (m,25H) 2.27-2.64 (m, 3H) 2.93 (s, 1H) 3.28-3.69 (m, 4H) 3.71-3.87 (m, 5H)3.94 (s, 3H) 4.53-4.69 (m, 1H) 4.83-5.01 (m, 1H) 6.90 (s, 1H) 6.97 (d,J=2.44 Hz, 1H) 7.08-7.15 (m, 1H) 7.50-7.66 (m, 3H) 7.79 (d, J=1.53 Hz,1H) 7.93 (d, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[3-(dimethylamino)-1-piperidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylpropyl)sulfonyl]-

ESI-MS m/e 741 (MH⁺). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.01-1.15 (m,3H) 1.19-1.61 (m, 7H) 1.64-2.28 (m, 15H) 2.41-2.76 (m, 5H) 2.82-2.96 (m,1H) 3.35-3.83 (m, 3H) 3.78-3.91 (m, 3H) 3.90-3.98 (s, 3H) 4.19-4.40 (m,1H) 4.54-4.71 (m, 1H) 4.78-4.98 (m, 1H) 6.84-6.96 (m, 1H) 6.95-7.01 (m,1H) 7.07-7.15 (m, 1H) 7.50-7.58 (m, 1H) 7.59-7.87 (m, 3H) 7.90-7.99 (m,1H) 10.02-10.36 (m, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-N-[(1-methylpropyl)sulfonyl]-

ESI-MS m/e 744 (MH⁺) 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.01-1.15 (m,2H) 1.23 (d, J=15.26 Hz, 1H) 1.33-1.59 (m, 5H) 1.70-2.31 (m, 13 H)2.36-2.53 (m, 1H) 2.83-3.49 (m, 10H) 3.81-3.93 (m, 3H) 3.94 (s, 3H) 4.60(d, J=15.26 Hz, 1H) 4.79-5.00 (m, 1H) 6.85 (s, 1H) 6.95 (s, 1H) 7.12(dd, J=8.55, 2.75 Hz, 1H) 7.50-7.81 (m, 4H) 7.86-7.99 (m, 1H)10.29-10.54 (m, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-ethyl-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester. tert-butyl13-cyclohexyl-6-((2E,Z)-3-(dimethylamino)-2-(ethoxycarbonyl)-2-propenoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(370 mg, 0.604 mmol) was dissolved in ethanol (1.7 ml) and the oxylatesalt of ethyl hydrazine (100 mg, 0.664 mg) was added to the reaction atroom temperature. The reaction was heated to 80 deg C for 3 hrs. Thereaction was diluted with chloroform and washed with water. The organicphase was concentrated under reduced pressure and purified by prep HPLCunder the following conditions: Shimadzu preparative HPLC usingDiscovery VP software: % A=10% acetonitrile, 90% water, 0.1% TFA; %B=90% acetonitrile, 10% water, 0.1% TFA; Initial % B=30; Final % B=100;Gradient=12 min; Runtime=20 min; Flow rate=40 ml/min; Column=WatersSunfire 30×100 mm S5. This afforded the title compound (265 mg, 72%) asa yellow paste. MS m/z 610 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester

tert-Butyl13-cyclohexyl-6-((2E,Z)-3-(dimethylamino)-2-(ethoxycarbonyl)-2-propenoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(180 mg, 0.294 mmol) was dissolved in a solution of ethanol (1 ml),triethyl amine (82.0 uL, 0.588 mmol) and the hydrochloride salt of2-propyl hydrazine (36 mg, 0.323 mmol). The reaction was heated in amicrowave at 160° C. for 2 hours and then concentrated. The resultingsolid was purified by preparative HPLC under the following conditions:Shimadzu preparative HPLC using Discovery VP software: % A=10%acetonitrile, 90% water, 0.1% TFA; % B=90% acetonitrile, 10% water, 0.1%TFA; Initial % B=30; Final % B=100; Gradient=12 min; Runtime=20 min;Flow rate=40 ml/min; Column=Waters Sunfire 30×100 mm S5. Homogeneousfractions were combined and evaporated in vacuo to afford the titlecompound (127 mg, 69%) as a yellow paste. MS m/z 624 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,6-(4-carboxy-1-ethyl-1H-pyrazol-5-yl)-13-cyclohexyl-3-methoxy-,10-(1,1-dimethylethyl) ester

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-ethyl-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester (250 mg, 0.410 mmol) was dissolved in 12 mL ofmethanol/THF (1:1, v/v) and 1M aqueous sodium hydroxide (6 ml, 6 mmol)was added to the reaction. The resulting mixture was stirred at roomtemperature for 18 hr, and then diluted with 1M aqueous hydrochloricacid and the product was extracted with chloroform. The organic phasewas dried over Na₂SO₄, filtered and the filtrate concentrated in vacuuoto give the title compound (251 mg, 100%) that was used in subsequentsteps without further purification. MS m/z 612 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester

To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,6-(4-carboxy-1-ethyl-1H-pyrazol-5-yl)-13-cyclohexyl-3-methoxy-,10-(1,1-dimethylethyl) ester (120 mg, 0.206 mmol) in THF (1 mL) at 60°C. was added carbonyldiimidazole (47 mg, 0.288 mmol) and the solutionstirred for 1 hour. Morpholine (36 mg, 0.412 mmol) and DBU (33 mg, 0.268mmol) were then added and the reaction was heated for a further 1 hr andwas then allowed to stir to room temperature overnight. The reaction wasthen diluted with 1M aqueous hydrochloric acid and the resultant mixturewas extracted with chloroform. The extracts were dried over Na₂SO₄,filtered and then concentrated in vacuo to provide the title compound inquantitative yield. MS m/z 651 (MH⁻).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester (61 mg, 0.094 mmol) was dissolved intrifluoroacetic acid (2 mL) and stirred at room temperature for 3 hoursand the mixture was then concentrated in vacuuo. Residualtrifluoroacetic acid was removed by azeotroping with benzene and thefinal product was dried in vacuuo to provide the title compound, (56 mg,100%) that was used without further purification. MS m/z 595 (MH⁺).

Morpholine,4-[[13-cyclohexyl-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-10-yl]carbonyl]-

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-,(60 mg, 0.092 mmol) was dissolved in THF (0.9 mL) andcarbonyldiimidazole (21 mg, 0.130 mmol) was added. The resultant mixturewas then stirred at 60° C. for 1 hr. Upon cooling to room temperatureunder a nitrogen atmosphere, morpholine (40 mg, 0.460 mmol) and DBU(0.012 mL, 0.120 mmol) were added. The reaction was heated for 1 hr thenallowed to stir to room temperature overnight. The resulting mixture wasfiltered and the resultant filtrate was purified by preparative HPLCunder the following conditions: Shimadzu preparative HPLC usingDiscovery VP software: % A=10% acetonitrile, 90% water, 0.1% TFA; %B=90% acetonitrile, 10% water, 0.1% TFA; Initial % B=30; Final % B=100;Gradient=12 min; Runtime=20 min; Flow rate=40 mL/min; Column=WatersSunfire 30×100 mm S5. This afforded the title compound (31 mg, 51%) as ayellow paste. MS m/z 664 (MH⁺).

The following compounds were synthesized by an analogous sequence asdescribed above for 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-:

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-

MS m/z 581 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-

MS m/z 620 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[1-(1-methylethyl)-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-

MS m/z 609 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-,(56 mg, 0.094 mmol) was dissolved in THF (0.9 mL) andcarbonyldiimidazole (21 mg, 0.129 mmol) added to the reaction at 60° C.and the resultant mixture was stirred for 1 hr. Propane-2-sulfonamide(57 mg, 0.246 mmol) and DBU (15 mg, 0.120 mmol) were then added to thereaction and the mixture was heated for a further 1 hour, then allowedto stir to room temperature for 18 hours. The resulting mixture wasfiltered and the filtrate purified by prep HPLC under the followingconditions: Shimadzu preparative HPLC using Discovery VP software: %A=10% acetonitrile, 90% water, 0.1% TFA; % B=90% acetonitrile, 10%water, 0.1% TFA; Initial % B=30; Final % B=100; Gradient=12 min;Runtime=20 min; Flow rate=40 mL/min; Column=Waters Sunfire 30×100 mm S5.This afforded the title compound (40 mg, 61%) as a yellow paste. MS m/z700 (MH⁺).

The following compounds were synthesized by an analogous method asdescribed above for 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-:

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-ethyl-4-[(4-methyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-3-methoxy-N-(1-pyrrolidinylsulfonyl)-

MS m/z 740 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-ethyl-4-[(4-methyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

MS m/z 713 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-N-(1-pyrrolidinylsulfonyl)-

MS m/z 727 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-

MS m/z 701 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-

MS m/z 687 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-

MS m/z 726 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-

MS m/z 723 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-N-(1-pyrrolidinylsulfonyl)-

MS m/z 752 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-[1-(1-methylethyl)-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-

MS m/z 715 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-

Dissolve 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester (2.00 g, 3.21 mmol) in 1,2-dichloroethane (6.41mL), place reaction under a nitrogen atmosphere, then addtrifluoroacetic acid (6.41 ml). Stir reaction at room temperature undera nitrogen atmosphere for 2 hours. Remove volatiles in vacuuo anddissolve the reaction product in benzene and remove in vacuuo to aid inremoval of trace TFA. Repeat dissolution in benzene and removal invacuuo. Dry sample at room temperature in vacuuo to obtain the titlecompound (1.92 g, 100% yield) as a yellow solid. 1H NMR (500 MHz,CHLOROFORM-D) δ ppm 0.48 (br s, 3H) 1.12-1.65 (m, 9H) 1.72-2.19 (m, 7H)2.87 (t, J=11.29 Hz, 1H) 3.91 (s, 3H) 4.22 (m, 1H) 4.32 (br.s, 2H) 4.73(br.s, 1H) 4.97 (br.s, 1H) 6.70 (s, 1H) 6.94 (d, J=2.14 Hz, 1H) 7.08(dd, J=8.55, 2.44 Hz, 1H) 7.52 (m, 2H) 7.64 (d, J=8.24 Hz, 1H) 7.82 (d,J=8.24 Hz, 1H) 7.96 (s, 1H). LCMS 566 m/z (MH−).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-1-(1-methylethyl)-,ethyl ester. Dissolve 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-(1.00g, 1.76 mmol) in THF (5.87 mL). Carbonyldiimidazole (857 mg, 5.28 mmol)was added to the reaction. The reaction was placed under a nitrogenatmosphere and stirred at room temperature for 45 minutes then heated toreflux for 1 hour. The reaction was cooled under a nitrogen atmosphereand propane-2-sulfonamide (868 mg, 7.05 mmol) was added to the reactionfollowed by DBU (0.797 mL, 5.28 mmol). The reaction was immerse in oilbath at 80 deg C under nitrogen atmosphere and heated overnight at 70-80deg C. The reaction was diluted with ethyl acetate (50 mL) and theorganic layer washed sequentially with 1.0N aqueous hydrochloric acid(50 mL), 0.1M aqueous NaH2PO4 (50 mL) and brine (25 mL). The organiclayer was dried over MgSO4, filtered and volatiles removed in vacuuo toyield a yellow foam which was dried in vacuuo at room temperatureovernight to yield 1.03 g (1.57 mmol, 87%) of the title compound as ayellow amorphous solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.40 (br s,3H) 1.12-1.70 (m, 15H) 1.72-2.18 (m, 7H) 2.84 (t, J=11.29 Hz, 1H) 3.90(s, 3H) 4.11 (m, 1H) 4.26 (m, 3H) 4.66 (br.s, 1H) 4.97 (br.s, 1H) 6.68(s, 1H) 6.94 (d, J=2.14 Hz, 1H) 7.08 (m, 2H) 7.52 (d, J=8.24 Hz, 1H)7.67 (d, J=8.24 Hz, 1H) 7.80 (d, J=8.24 Hz, 1H) 7.89 (s, 1H). LCMS 671m/z (MH−).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl-1-(1-methylethyl)-

Dissolve 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(1-methylethyl)-,ethyl ester (1.20 g, 1.78 mmol) was dissolved in THF (15.0 mL) andmethanol (15.0 mL) was added to the reaction followed by 1N aqueoussodium hydroxide (15.0 mL). The reaction was capped under a nitrogenatmosphere and stirred at room temperature for 18 hrs. The reaction wasdiluted with ethyl acetate (25.0 mL) and washed with 1.0N aqueoushydrochloric acid (2×20 mL). The organic layer was concentrated invacuuo using a rotary evaporator to yield the title compound as a yellowsolid (1.15 g, 100%).

MS m/z 645 (MH⁺).

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.46 (br s, 3H) 1.12-1.70 (m, 12 H)1.72-2.15 (m, 7H) 2.85 (t, J=11.29 Hz, 1H) 3.90 (s, 3H) 4.26 (m, 1H)4.62 (br.s, 1H) 4.99 (br.s, 1H) 6.69 (s, 1H) 6.96 (d, J=2.14 Hz, 1H)7.06 (dd, J=8.55, 2.44 Hz, 1H) 7.50 (m, 2H) 7.80 (m, 2H) 7.85 (s, 1H)9.09 (br s, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-(1-methylethyl)-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(1-methylethyl)-(125mg, 0.194 mmol) in DMSO (1.94 mL), TBTU (124 mg, 0.388 mmol) and DIPEA(0.100 mg, 0.775 mmol) were added. The reaction mixture was stirred atRT for 15 min. Then morpholine (68 mg, 0.775 mmol) was added. Thesolution was stirred at RT for overnight. The reaction mixture waspurified by prep HPLC column using CH₃CN/H₂O/TFA as solvent system.Fractions were collected and concentrated under speedvac overnight toyield the title compound as a yellow solid (82 mg, 0.114 mmol, 59%yield). MS m/z 714 (M−H⁺). 1H NMR (500 MHz, CDCl3) δ ppm 1.20 (m, 1H)1.32-1.65 (m, 15H) 1.73-2.20 (m, 6H) 2.63-3.24 (m, 7H) 3.50 (br m, 2H)3.93 (s, 3H) 4.07 (m, 1H) 4.58 (m, 2H) 4.90 (m, br, 1 H) 6.78 (s, 1H)6.93 (d, J=2.44 Hz, 1H) 7.13 (dd, J=8.55, 2.75 Hz, 1H) 7.53-7.64 (m, 2H)7.71 (m, 2H) 7.93 (d, J=8.55 Hz, 1H) 10.15 (s, br, 1H).

The following compounds were synthesized by an analogous method asdescribed above for 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-(1-methylethyl)-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-:

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(2,6-dimethyl-4-morpholinyl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

1H NMR (500 MHz, CDCl3) δ ppm 0.61-0.92 (m, 6H) 1.23 (m, 1H) 1.35-1.70(m, 15H) 1.73-2.20 (m, 6H) 2.88 (m, 1H) 3.12-3.70 (m, 6H) 3.92 (s, 3H)4.09 (m, 1H) 4.58 (m, 2H) 4.91 (m, br, 1H) 6.75 (s, 1H) 6.92 (d, J=2.44Hz, 1H) 7.12 (dd, J=8.55, 2.75 Hz, 1H) 7.53-7.68 (m, 2H) 7.75 (m, 2H)7.92 (d, J=8.55 Hz, 1H) 10.10 (s, br, 1H). LCMS: m/e 742 (M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-

1H NMR (500 MHz, CDCl3) δ ppm 0.02 (m, 2H) 0.82 (m, 2H) 1.20-1.82 (m,16H) 1.91-2.18 (m, 6H) 2.39-2.70 (m, 4H) 2.88 (m, 1H) 2.96-3.59 (m, 5H)3.94 (s, 3H) 4.06 (m, 1H) 4.62 (m, 2H) 4.85 (m, br, 1H) 6.92 (m, 2H)7.12 (dd, J=8.55, 2.75 Hz, 1H) 7.53-7.69 (m, 3H) 7.86 (br s, 1H) 7.92(d, J=8.55 Hz, 1H) 10.10 (s, br, 1H). LCMS: m/e 753 (M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

1H NMR (500 MHz, CDCl3) δ ppm 0.02 (m, 1H) 1.10-1.59 (m, 19H) 1.91-2.49(m, 8H) 2.80-3.69 (m, 4H) 2.88 (m, 1H) 3.81-4.41 (s, 7H) 4.62 (m, 2H)4.90 (m, br, 1H) 6.97 (m, 2H) 7.10 (m, 1H) 7.53-7.67 (m, 2H) 7.71-7.95(m, 3H) 10.20 (s, br, 1H). LCMS: m/e 753 (M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(3-methyl-3,6-diazabicyclo[3.1.1]hept-6-yl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-

1H NMR (500 MHz, CDCl3) δ ppm 1.17-1.85 (m, 15H) 1.90-2.18 (m, 9H)2.59-2.99 (m, 6H) 3.35-4.10 (m, 8H) 4.66-5.00 (m, 3H) 6.92 (m, 2H) 7.12(dd, J=8.55, 2.75 Hz, 1H) 7.50-7.69 (m, 3H) 7.75-8.01 (m, 2H) 10.00 (s,br, 1H). LCMS: m/e 739 (M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-]-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]

1H NMR (500 MHz, CDCl3) δ ppm 0.021 (m, 2H) 0.81 (m, 2H) 1.20-1.86 (m,16H) 1.91-2.17 (m, 6H) 2.41-2.71 (m, 4H) 2.88 (m, 1H) 2.97-3.70 (m, 5H)3.94 (s, 3H) 4.08 (m, 1H) 4.62 (m, 2H) 4.85 (m, br, 1H) 6.94 (m, 2H)7.12 (dd, J=8.55, 2.75 Hz, 1H) 7.52-7.69 (m, 3H) 7.80-7.95 (m, 2H) 10.10(s, br, 1H). LCMS: m/e 753 (M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-(1-methylethyl)-4-[(3,4,5-trimethyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-

1H NMR (500 MHz, CDCl3) δ ppm 1.20-1.82 (m, 22H) 1.91-2.18 (m, 6H) 2.50(br s, 3H) 2.90 (m, 1H) 3.35-3.69 (m, 7H) 3.92 (s, 3H) 4.02 (m, 1H) 4.61(br m, 1H) 4.93 (br m, 1H) 6.80 (br s, 1H) 6.95 (s, 1H) 7.11 (dd,J=8.55, 2.75 Hz, 1H) 7.51-7.65 (m, 3H) 7.80 (br s, 1H) 7.90 (d, J=8.55Hz, 1H) 10.20 (s, br, 1H). LCMS: m/e 755 (M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

1H NMR (500 MHz, CDCl3) δ ppm 1.15-1.82 (m, 19H) 1.91-2.18 (m, 3H) 2.88(m, 1H) 3.12-3.80 (m, 9H) 3.92 (s, 3H) 4.05 (m, 1H) 4.40 (m, 2H) 4.61(br d, 1H) 4.92 (br d, 1H) 6.78 (s, 1H) 6.91 (d, J=2.44 Hz, 1H) 7.13(dd, J=8.55, 2.75 Hz, 1H) 7.59-7.65 (m, 2H) 7.77 (m, 2H) 7.93 (d, J=8.55Hz, 1H) 10.10 (s, br, 1H). LCMS: m/e 756 (M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(3-endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

1H NMR (500 MHz, CDCl3) δ ppm −0.25 (m, 1H) 0.52 (m, 1H) 1.04 (s, 3H)1.15-1.82 (m, 24 H) 1.91-2.18 (m, 4H) 2.89 (m, 1H) 3.29 (m, 1H) 3.62 (m,1H) 3.92 (s, 3H) 4.06 (m, 1H) 4.54-4.71 (m, 2H) 5.00 (br d, 1H) 6.82 (brs, 1H) 6.91 (d, J=2.75 Hz, 1H) 7.12 (dd, J=8.55, 2.75 Hz, 1H) 7.50-7.60(m, 2H) 7.70 (m, 1H) 7.80-7.95 (m, 2H) 10.20 (s, br, 1H). LCMS: m/e 768(M+H), ret time 2.75 min (method 1).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(3-methyl-8-azabicyclo[3.2.1]oct-2-en-8-yl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-:m/e 750 (M+H), ret time 2.89 min (method 1).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-

1H NMR (500 MHz, CDCl3) δ ppm 1.21 (m, 1H) 1.32-1.70 (m, 15H) 1.73-2.20(m, 6H) 2.72-3.47 (m, 8H) 3.88-4.17 (m, 10H) 4.61 (m, 1H) 4.95 (m, br,1H) 6.80 (br d, 1H) 6.93 (br s, 1H) 7.12 (dd, J=8.55, 2.75 Hz, 1H)7.53-7.64 (m, 2H) 7.71-7.96 (m, 3H) 10.15 (s, br, 1H). LCMS: m/e 758(M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-(1-methylethyl)-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-

LCMS: m/e 728 (M+H), ret time 3.59 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(2,6-dimethyl-4-morpholinyl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-

LCMS: m/e 756 (M+H), ret time 3.71 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-

LCMS: m/e 767 (M+H), ret time 3.35 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-

LCMS: m/e 767 (M+H), ret time 3.31 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-

LCMS: m/e 767 (M+H), ret time 3.38 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(2-methylpropyl)sulfonyl]-6-[1-(1-methylethyl)-4-[(3,4,5-trimethyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-

LCMS: m/e 769 (M+H), ret time 3.32 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-

LCMS: m/e 770 (M+H), ret time 3.65 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-

LCMS: m/e 772 (M+H), ret time 3.61 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(3-methyl-8-azabicyclo[3.2.1]oct-2-en-8-yl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-

LCMS: m/e 764 (M+H), ret time 3.69 min (method 2).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester

tert-butyl13-cyclohexyl-6-((2E,Z)-3-(dimethylamino)-2-(ethoxycarbonyl)-2-propenoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(1.20 g, 1.96 mmol) was dissolved in a solution of ethanol (6.53 mL),triethyl amine (0.396 g, 3.92 mmol), and (2,2,2-trifluoroethyl)hydrazine(0.246 g, 2.15 mmol). The reaction was heated in a microwave at 160 degC for 2 hours and concentrated. The resulting solid was purified by prepHPLC under the following conditions: Shimadzu prep. HPLC using DiscoveryVP software: % A=10% acetonitrile, 90% water, 0.1% TFA; % B=90%acetonitrile, 10% water, 0.1% TFA; Initial % B=30; Final % B=100;Gradient=12 min; Runtime=20 min; Flow rate=40 ml/min; Column=WatersSunfire 30×100 mm S5. This afforded the title compound (1.09 g, 84%) asa yellow paste. MS m/z 664 (MH⁺).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-3-methoxy-

Dissolve 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester (1.20 g, 1.81 mmol) in 1,2-dichloroethane (3.62mL), place reaction under a nitrogen atmosphere, then addtrifluoroacetic acid (3.62 mL). Stir reaction at room temperature undera nitrogen atmosphere for 2 hours. Remove volatiles in vacuuo anddissolve the reaction product in benzene and remove in vacuuo to aid inremoval of trace TFA. Repeat dissolution in benzene and removal invacuuo. Dried sample at room temperature in vacuuo to obtain the titlecompound (0.923 g, 100% yield) as a yellow solid. 1H NMR (500 MHz,CHLOROFORM-D) δ ppm 1.20-1.62 (m, 7H) 1.70-2.19 (m, 6H) 2.87 (m, 1H)3.91 (s, 3H) 4.12-4.45 (m, 4H) 4.76 (br.s, 1H) 4.97 (br.s, 1H) 6.82 (s,1H) 6.96 (d, J=2.14 Hz, 1H) 7.10 (dd, J=8.55, 2.44 Hz, 1H) 7.56 (d,J=8.85 Hz, 1H) 7.78 (d, J=8.24 Hz, 1H) 7.90 (m, 2H) 8.11 (s, 1H). LCMS608 m/z (MH+).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(2,2,2-trifluoroethyl),ethyl ester

Dissolve 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-3-methoxy-(800mg, 1.32 mmol) in THF (4.39 mL). Carbonyldiimidazole (640 mg, 3.95 mmol)was added to the reaction. The reaction was placed under a nitrogenatmosphere and stirred at room temperature for 45 minutes then heated toreflux for 1 hour. The reaction was cooled under a nitrogen atmosphereand propane-2-sulfonamide (649 mg, 5.27 mmol) was added to the reactionfollowed by DBU (0.595 mL, 3.95 mmol). The reaction was immerse in oilbath at 80 deg C. under nitrogen atmosphere and heated overnight at70-80 deg C. The reaction was diluted with ethyl acetate (50 mL) and theorganic layer washed sequentially with 1.0N aqueous hydrochloric acid(50 mL), 0.1M aqueous NaH2PO4 (50 mL) and brine (25 mL). The organiclayer was dried over MgSO4, filtered and volatiles removed in vacuuo toyield a yellow foam which was dried in vacuuo at room temperatureovernight to yield the title compound (949 mg, 100%) as a yellowamorphous solid. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.20-1.62 (m, 13H) 1.70-2.18 (m, 6H) 2.87 (m, 1H) 3.90 (s, 3H) 4.05 (m, 1H) 4.10-4.40(m, 4H) 4.73 (br.s, 1H) 4.99 (br.s, 1H) 6.82 (s, 1H) 6.93 (d, J=2.14 Hz,1H) 7.10 (dd, J=8.55, 2.44 Hz, 1H) 7.45 (br d, 1H) 7.52 (d, J=8.85 Hz,1H) 7.80 (br s, 1H) 7.88 (d, J=8.85 Hz, 1H) 8.02 (s, 1H) 8.60 (br s,1H). LCMS 713 m/z (MH+).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(2,2,2-trifluoroethyl)

Dissolve 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(2,2,2-trifluoroethyl),ethyl ester (0.816 g, 1.15 mmol) in THF (2.86 mL) and methanol (2.86 mL)was added to the reaction followed by 1N aqueous sodium hydroxide (2.29mL). The reaction was capped under a nitrogen atmosphere and stirred atroom temperature for 18 hrs. The reaction was diluted with ethyl acetate(25.0 mL) and washed with 1.0N aqueous hydrochloric acid (2×20 mL). Theorganic layer was concentrated in vacuuo using a rotary evaporator toyield the title compound as a yellow solid (0.784 g, 100%). 1H NMR (500MHz, CHLOROFORM-D) δ ppm 1.20-1.62 (m, 10H) 1.70-2.18 (m, 6H) 2.87 (m,1H) 3.90 (s, 3H) 4.05 (m, 1H) 4.27 (br m, 2H) 4.73 (br.s, 1H) 4.99(br.s, 1H) 6.82 (s, 1H) 6.93 (d, J=2.14 Hz, 1H) 7.10 (dd, J=8.55, 2.44Hz, 1H) 7.45 (br d, 1H) 7.52 (d, J=8.85 Hz, 1H) 7.80 (br s, 1H) 7.88 (d,J=8.85 Hz, 1H) 8.02 (s, 1H) 8.60 (br s, 1 H). LCMS 685 m/z (MH+).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[4-(4-morpholinylcarbonyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(2,2,2-trifluoroethyl)(90 mg, 0.131 mmol) in DMSO (1.31 mL), TBTU (84 mg, 0.263 mmol) andDIPEA (68 mg, 0.526 mmol) were added. The reaction mixture was stirredat RT for 15 min. Then morpholine (46 mg, 0.526 mmol) was added. Thesolution was stirred at RT for overnight. The reaction mixture waspurified by prep HPLC column using CH₃CN/H₂O/TFA as solvent system.Fractions were collected and concentrated under speedvac overnight toyield the title compound as a yellow solid (53 mg, 0.070 mmol, 53%yield). MS m/z 754 (M−H⁺); 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.22 (m,1H) 1.33-1.57 (m, 9H) 1.70-2.18 (m, 6 H) 2.59 (br m, 1H) 2.70-2.95 (m,6H) 3.05-3.21 (m, 2H) 3.92 (s, 3H) 4.07 (m, 1H) 4.73 (br.d, 1H) 4.76 (brm, 2H) 4.86 (br.d, 1H) 6.90 (s, 1H) 6.94 (d, J=2.14 Hz, 1H) 7.15 (dd,J=8.55, 2.44 Hz, 1H) 7.60 (d, J=8.85 Hz, 1H) 7.63 (d, J=8.24 Hz, 1H)7.67 (s, 1H) 7.80 (s, 1H) 7.93 (d, J=8.85 Hz, 1H).

The following compounds were synthesized by an analogous method asdescribed above for 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[4-(4-morpholinylcarbonyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-:

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.64-0.90 (m, 5H) 1.16-1.28 (m, 2H)1.33-1.57 (m, 9 H) 1.73-2.18 (m, 8H) 2.30 (br m, 1H) 2.87 (m, 2H)3.05-3.29 (m, 3H) 3.94 (s, 3 H) 4.07 (m, 1H) 4.58 (br.d, 1H) 4.72 (br m,2H) 4.93 (br.d, 1H) 6.87-6.96 (m, 1H) 7.15 (dd, J=8.55, 2.44 Hz, 1H)7.52-7.68 (m, 2H) 7.72-7.85 (m, 2H) 7.93 (m, 1H) 8.48 (br s, 1H). LCMS:m/e 782 (M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.19 (br s, 1H) 0.80 (br s, 1H)1.25-1.62 (m, 11H) 1.76-2.18 (m, 7H) 2.48 (br m, 1H) 2.62 (br s, 3H)2.88 (m, 2H) 2.95-3.50 (m, 4H) 3.92 (s, 3H) 4.06 (m, 1H) 4.59 (br.d, 1H)4.86 (br m, 3H) 6.93 (s, 1H) 7.05 (br s, 1 H) 7.17 (dd, J=8.55, 2.44 Hz,1H) 7.60 (d, J=8.85 Hz, 1H) 7.65 (d, J=8.24 Hz, 1H) 7.86 (br s, 1H) 7.96(m, 2H) 10.0 (br s, 1H). LCMS: m/e 793 (M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.10-1.59 (m, 14H) 1.70-2.18 (m,7H) 2.38 (m, 1H) 2.80-3.85 (m, 8H) 3.95 (s, 3H) 4.03 (m, 1H) 4.58 (br.d,1H) 4.98 (br.m, 3H) 6.87-6.96 (m, 1H) 7.15 (dd, J=8.55, 2.44 Hz, 1H)7.52-7.68 (m, 2H) 7.72-7.85 (m, 2H) 7.93 (m, 1H) 8.48 (br s, 1H). LCMS:m/e 793 (M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.18 (br s, 1H) 0.81 (br s, 1H)1.26-1.62 (m, 11H) 1.80 (m, 2H) 1.94-2.18 (m, 5H) 2.44 (br m, 1H) 2.62(br s, 3H) 2.90 (m, 2H) 2.95-3.55 (m, 4H) 3.92 (s, 3H) 4.06 (m, 1H) 4.59(br.d, 1H) 4.86 (br m, 3H) 6.92 (s, 1H) 7.03 (br s, 1H) 7.17 (dd,J=8.55, 2.44 Hz, 1H) 7.58-7.65 (m, 1H) 7.86 (br s, 1H) 7.96 (m, 2H) 10.0(br s, 1H). LCMS: m/e 793 (M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-(2,2,2-trifluoroethyl)-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.05-1.57 (m, 15H) 1.70-2.12 (m,7H) 2.30-2.99 (m, 6H) 3.20-3.65 (m, 4 H) 3.92 (s, 3H) 4.03 (m, 1H) 4.60(br.d, 1H) 4.65-4.98 (br.m, 3H) 6.95 (m, 2H) 7.15 (dd, J=8.55, 2.44 Hz,1H) 7.57 (m, 2H) 7.71 (s, 1H) 7.82 (br s, 1H) 7.93 (d, J=8.85 Hz, 1H).LCMS: m/e 795 (M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[4-(3-oxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.12-1.53 (m, 13H) 1.70-2.40 (m,9H) 2.87 (m, 1H) 3.03-3.62 (m, 6H) 3.92 (s, 3H) 4.07 (m, 1H) 4.73 (br.d,1H) 4.76 (br m, 2H) 4.86 (br.d, 1H) 6.90 (s, 1H) 6.94 (d, J=2.14 Hz, 1H)7.15 (dd, J=8.55, 2.44 Hz, 1H) 7.60 (d, J=8.85 Hz, 1H) 7.63 (d, J=8.24Hz, 1H) 7.67 (s, 1H) 7.80 (s, 1H) 7.93 (d, J=8.85 Hz, 1 H). LCMS: m/e794 (M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

1H NMR (500 MHz, CDCl3) δ ppm −0.25 (m, 1H) 0.52 (m, 1H) 1.06 (s, 3H)1.15-1.82 (m, 18H) 1.91-2.18 (m, 4H) 2.88 (m, 1H) 3.32 (m, 1H) 3.60 (m,1H) 3.93 (s, 3H) 4.07 (m, 1H) 4.56 (br d, 1H) 4.82 (m, 2H) 4.97 (br d,1H) 6.82 (br s, 2H) 7.16 (dd, J=8.55, 2.75 Hz, 1H) 7.60 (d, J=8.55 Hz,1H) 7.70 (d, J=8.24 Hz, 1H) 7.84-7.92 (m, 3H). LCMS: m/e 808 (M+H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-

1H NMR (500 MHz, CDCl3) δ ppm 1.21 (m, 1H) 1.32-1.70 (m, 9H) 1.73-2.20(m, 6H) 2.72-3.40 (m, 13H) 3.92 (m, 3H) 4.10 (m, 1H) 4.60 (m, 1H) 4.82(m, br, 3H) 6.85-6.96 (m, 2H) 7.17 (dd, J=8.55, 2.75 Hz, 1H) 7.53-7.72(m, 3H) 7.80-7.96 (m, 2H). LCMS: m/e 798 (M+H).

Methyl 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate

To a solution of5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid(1.00 g, 4.38 mmol) in benzene (5.83 mL) and methanol (2.92 mL) at roomtemperature was added 2M trimethylsilyldiazomethane (8.75 mL). Theresulting solution was stirred at room temperature for 3 hours. Solventwas removed at reduced pressure on a rotory evaporator to yield thetitle compound (1.06 g, 4.38 mmol, 100% yield) as a white solid. MS m/z243 (MH⁺). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 3.82 (s, 3H) 3.89 (s,3H).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-,1,1-dimethylethyl ester

In a microwave tube, 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester(1.00 g, 1.37 mmol), methyl5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (497 mg,2.05 mmol) and bis(dibenzylideneacetone) palladium (78 mg, 0.136 mmol)were added. It was then sealed, degassed and flushed with nitrogen.1,4-dioxane (6.83 mL) was added. The reaction mixture was heated at 160°C. under microwave condition for 3 hours. It was then filtered and thefiltrate was concentrated. The residue was purified on a Shimadzu highpressure liquid chromatography system employing Discovery VP softwareinterfaced with a SCL-10A controller, SIL-10A autosampler and FRC-10Afraction collector. The sample was dissolved in acetonitrile/DMF (1:1)(8 mL) purified using a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mmcolumn and monitored using a SPD-10AV UV-Vis detector at a detector wavelength of 220 nM. The elution conditions employed a flow rate of 25mL/min, a gradient of 25% solvent A/75% solvent B to 0% solvent A/100%solvent B, a gradient time of 10 minutes with a run time of 20 minutesusing % A=10% acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile,10% water, 0.1% TFA solvent system. The product-containing fractionswere collected and concentrated to give title compound as a yellow solid(547 mg, 0.842 mmol, 61% yield). MS m/z 650 (MH⁺). 1H NMR (500 MHz,CHLOROFORM-D) δ ppm 1.06-2.29 (m, 19H) 2.85 (m, 1H) 3.30 (s, br, 3H)3.78 (s, br, 3H) 3.91 (s, 3H) 4.76 (m, br, 1H) 4.97 (m, br, 1H) 6.80 (s,1H) 6.93 (d, J=2.44 Hz, 1H) 7.11 (dd, J=8.55, 2.75 Hz, 1H) 7.56 (d,J=8.54 Hz, 1H) 7.82 (dd, J=8.24, 1.22 Hz, 1H) 7.91 (dd, J=8.24, 1.22 Hz,1H) 7.98 (s, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-

To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-,1,1-dimethylethyl ester (547 mg, 0.842 mmol) in 1,2-dichloroethane (5mL), TFA (5 mL) was added. The reaction mixture was stirred at RT for 4hours. Volatiles were removed on a rotary evaporator to give the titlecompound as a brownish thick oil as crude product (500 mg, 0.842 mmol,100% yield). MS m/z 594 (MH⁺). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm1.06-2.28 (m, 10H) 2.86 (m, 1H) 3.30 (s, br, 3H) 3.78 (s, br, 3H) 3.91(s, 3H) 4.75 (m, br, 1H) 4.96 (m, br, 1H) 6.80 (s, 1H) 6.93 (d, J=2.44Hz, 1H) 7.10 (dd, J=8.55, 2.75 Hz, 1H) 7.54 (d, J=8.54 Hz, 1 H) 7.81(dd, J=8.24, 1.22 Hz, 1H) 7.91 (dd, J=8.24, 1.22 Hz, 1H) 7.97 (s, 1H).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-3-(trifluoromethyl)-,methyl ester

To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-(480mg, 0.809 mmol) in tetrahydrofuran (2.70 mL) was addedcarbonyldiimidazole (393 mg, 2.43 mmol). The reaction mixture was heatedat 60° C. for one hour and then allowed to cool. Propane-2-sulfonamide(398 mg, 3.23 mmol) and DBU (0.366 mL, 2.43 mmol) were added at roomtemperature, and the reaction mixture was then heated at 60° C. for 4hours. The resultant mixture was then diluted with 1N HCl (50 mL)solution and extracted with ethyl acetate (2×40 mL). The organic layerswere combined and concentrated on a rotory evaporator to give theproduct as an orange colored oil. This material was then purified bypreparative HPLC column using CH₃CN/H₂O/TFA as solvent system.Homogeneous fractions were collected and concentrated under reducedpressure. The title compound was obtained as a yellow solid, (492 mg,0.704 mmol, 87% yield). MS m/z 699 (MH⁺). 1H NMR (500 MHz, CHLOROFORM-D)δ ppm 1.16-1.61 (m, 10H) 1.69-2.21 (m, 6H) 2.86 (m, 1H) 3.34 (s, br, 3H)3.67 (s, br, 3H) 3.91 (s, 3H) 4.01-4.19 (m, 1H) 4.70 (m, br, 1H) 4.97(m, br, 1H) 6.70 (s, 1H) 6.94 (d, J=2.75 Hz, 1H) 7.09 (dd, J=8.55, 2.75Hz, 1H) 7.51 (dd, J=8.55, 1.22 Hz, 1H) 7.81 (d, J=1.22 Hz, 1H) 7.88 (d,J=8.55 Hz, 1H) 7.92 (d, J=8.55 Hz, 1H) 8.68 (s, 1H).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-3-(trifluoromethyl)-

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-3-(trifluoromethyl)-,methyl ester (0.300 g, 0.429 mmol) was dissolved in THF (1.07 mL) andmethanol (1.07 mL) was added followed by 1N aqueous sodium hydroxide(0.900 mL). The reaction was then placed under a nitrogen atmosphere andstirred at room temperature for 18 hrs. The mixture was then dilutedwith ethyl acetate (50.0 mL) and washed with 1.0 N aqueous hydrochloricacid (2×50 ml). The organic layer was concentrated in vacuuo using arotary evaporator to yield the title compound as a yellow solid (282 mg,0.412 mmol, 96%). MS m/z 685 (MH⁺). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm1.16-1.61 (m, 10H) 1.69-2.21 (m, 6H) 2.86 (m, 1H) 3.34 (s, br, 3H) 3.91(s, 3H) 4.01-4.19 (m, 1H) 4.70 (m, br, 1H) 4.99 (m, br, 1H) 6.70 (s, 1H)6.94 (d, J=2.75 Hz, 1H) 7.10 (dd, J=8.55, 2.75 Hz, 1H) 7.51 (dd, J=8.55,1.22 Hz, 1H) 7.81 (d, J=1.22 Hz, 1H) 7.88 (d, J=8.55 Hz, 1H) 7.92 (d,J=8.55 Hz, 1H) 9.00 (s, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-(4-morpholinylcarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-3-(trifluoromethyl)-(75mg, 0.11 mmol) in DMSO (1.1 mL), TBTU (70 mg, 0.22 mmol) and DIPEA(0.057 mL, 0.4444 mmol) were added. The reaction mixture was stirred atRT for 15 min. Then morpholine (38 mg, 0.44 mmol) was added. Thesolution was stirred at RT overnight. The reaction mixture was thenpurified by preparative HPLC using CH₃CN/H₂O/TFA as solvent system.Homogeneous fractions were collected and concentrated under reducedpressure to yield the title compound as a yellow solid, (67 mg, 0.089mmol, 81% yield). MS m/z 754 (M−H⁺). 1H NMR (500 MHz, MeOD) δ ppm1.18-1.52 (m, 10H) 1.75-2.25 (m, 6H) 2.63-3.26 (m, 9H) 3.50 (s, br, 3H)3.95 (s, 3H) 3.96-4.03 (m, 1H) 4.64 (d, br, 1H) 4.98 (m, br, 1H) 6.88(s, 1H) 6.94 (d, J=2.44 Hz, 1H) 7.15 (dd, J=8.55, 2.75 Hz, 1H) 7.55-7.65(m, 2H) 7.80 (s, br, 1H) 7.93 (d, J=8.55 Hz, 1H) 10.30 (s, br, 1H).

The following compounds were synthesized by an analogous method asdescribed above for 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-(4-morpholinylcarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-:

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

MS m/z 782 (M−H⁺). 1H NMR (500 MHz, MeOD) δ ppm 0.71 (s, br, 3H), 0.75(s, br, 3H) 1.18-1.52 (m, 10 H) 1.75-2.21 (m, 9H) 2.35 (m, 1H) 2.83-3.21(m, 3H) 3.50 (s, br, 3H) 3.95 (s, 3 H) 3.96-4.03 (m, 1H) 4.64 (d, br,1H) 5.02 (d, br, 1H) 6.81 (s, 1H) 6.94 (d, J=2.44 Hz, 1H) 7.13 (dd,J=8.55, 2.75 Hz, 1H) 7.55-7.65 (m, 2H) 7.80 (s, br, 1H) 7.93 (d, J=8.55Hz, 1H) 10.50 (s, br, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-

MS m/z 793 (M−H⁺). 1H NMR (500 MHz, MeOD) δ ppm 1.16-2.20 (m, 20H)2.40-2.99 (m, 7H) 3.22-3.71 (m, 3H) 3.90-4.11 (m, 7H) 4.63 (m, br, 1H)4.98 (m, br, 1H) 6.98 (m, 1H) 7.03 (m, 1H) 7.23 (m, 1H) 7.52-7.73 (m,3H) 7.82 (s, br, 1H) 10.10 (s, br, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-3-(trifluoromethyl)-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-

MS m/z 795 (M−H⁺). 1H NMR (500 MHz, MeOD) δ ppm 1.10-1.51 (m, 16H)1.71-2.50 (m, 11H) 2.59-2.94 (m, 5H) 3.50 (s, br, 3H) 3.96 (s, 3H) 4.63(m, br, 2H) 4.95 (m, br, 1H) 6.93 (m, 2H) 7.13 (m, 1H) 7.49-7.65 (m, 2H)7.82 (s, br, 1H) 7.93 (m, 1H) 10.10 (s, br, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylcarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-

MS m/z 780 (M−H⁺)

1H NMR (500 MHz, CDCl3) δ ppm 0.70 (m, 1H) 1.21-1.52 (m, 13H) 1.75-2.20(m, 8H) 2.30 (m, 1H) 2.79-2.98 (m, 3H) 3.11 (m, 1H) 3.87 (m, 1H) 3.98(s, br, 3 H) 4.05 (s, 3H) 4.61 (d, br, 1H) 4.89 (m, br, 1H) 6.85-6.98(m, 2H) 7.17 (dd, J=8.55, 2.75 Hz, 1H) 7.55-7.70 (m, 2H) 7.84-8.03 (m,1H) 7.93 (d, J=8.55 Hz, 1H) 10.45 (s, br, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-

MS m/z 798 (M−H⁺)

1H NMR (500 MHz, CDCl3) δ ppm 1.11-1.61 (m, 10H) 1.75-2.52 (m, 10H)2.81-3.60 (m, 9H) 3.95 (s, br, 3H) 4.03 (s, 3H) 3.95-4.03 (m, 1H) 4.65(d, br, 1H) 5.01 (m, br, 1H) 6.85 (br s, 1H) 6.97 (s, 1H) 7.15 (dd,J=8.55, 2.75 Hz, 1H) 7.50-7.71 (m, 2H) 7.79-7.93 (m, 2H) 10.40 (s, br,1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[(4-methyl-1-piperazinyl)carbonyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-

MS m/z 767 (M−H⁺)

1H NMR (500 MHz, CDCl3) δ ppm 1.13-1.58 (m, 10H) 1.75-2.12 (m, 6H)2.20-2.97 (m, 5H) 3.19-3.79 (m, 7H) 3.95 (s, 3H) 3.99 (br s, 3H)3.95-4.03 (m, 1H) 4.50 (m, br, 1H) 4.92 (m, br, 1H) 6.87-7.01 (m, 2H)7.11 (dd, J=8.55, 2.75 Hz, 1H) 7.50 (dd, J=8.55, 2.75 Hz, 1H) 7.59-7.80(m, 2H) 7.91 (br s, 1H) 10.50 (s, br, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-

MS m/z 793 (M−H⁺)

1H NMR (500 MHz, CDCl3) δ ppm 0.37 (br m, 1H) 0.83 (br m, 1H) 1.14-1.70(m, 11H) 1.75-2.16 (m, 7H) 2.35-2.70 (m, 4H) 2.86 (m, 2H) 3.20-3.79 (m,4H) 3.90-4.11 (m, 7H) 4.63 (d, br, 1H) 4.94 (m, br, 1H) 6.95-7.10 (m,2H) 7.15 (dd, J=8.55, 2.75 Hz, 1H) 7.53-7.70 (m, 3H) 7.81 (s, br, 1H)10.10 (s, br, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

MS m/z 793 (M−H⁺)

1H NMR (500 MHz, CDCl3) δ ppm 0.55 (br m, 1H) 1.14-1.70 (m, 13H)1.75-2.16 (m, 7H) 2.52-3.70 (m, 9H) 3.89-4.11 (m, 7H) 4.69 (d, br, 1H)5.00 (m, br, 1H) 6.95-7.15 (m, 3H) 7.50-7.81 (m, 4H) 10.20 (s, br, 1H).

Methyl 5-iodo-1,3-dimethyl-1H-pyrazole-4-carboxylate

To a solution of methyl 1,3-dimethyl-1H-pyrazole-4-carboxylate (154 mg,1 mmol) in dry tetrahydrofuran (10 mL) at −78° C., 2 M solution of BuLi(0.550 mL, 1.100 mmol) in pentane was added dropwise. The reactionmixture was then warmed to −45° C. and stirred for 1 h. It was thencooled to −78° C. and a solution of IODINE (279 mg, 1.100 mmol) in THF(2 mL) was added. The reaction mixture was warmed to RT and stirred for1 h. It was then quenched with saturated NH₄Cl solution and extractedwith ethyl acetate (2×25 mL). The organic layers were combined, washedwith brine, dried over MgSO₄, and then concentrated in vacuo. The crudeproduct was obtained as a brown thick oil. This material was thenpurified by preparative HPLC using CH₃CN/H₂O/TFA as solvent system.Homogeneous fractions were combined and concentrated in vacuo. Theconcentrate was then extracted with ethyl acetate and the extractscombined and dried over MgSO₄. The suspension was then filtered and thefiltrand evaporated under reduced pressure to give the title compound asa white solid, (137 mg, 0.460 mmol, 46.0% yield). MS m/z 281 (MH⁺),Retention time: 1.107 min. (basic). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm2.45 (s, 3 H) 3.84 (s, 3H) 3.91 (s, 3H).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1,3-dimethyl-1H-pyrazol-5-yl]-,1,1-dimethylethyl ester

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester(50 mg, 0.068 mmol), methyl5-iodo-1,3-dimethyl-1H-pyrazole-4-carboxylate (38.2 mg, 0.136 mmol) andBis(triphenylphosphine)-palladium(II) chloride (4.79 mg, 6.82 μmol) wereadded to a standard microwave tube. The vessel was then sealed, degassedand flushed with nitrogen. 1,4-Dioxane (2.0 mL) was added and theresultant mixtue was heated at 120° C. under microwave conditions for 2h. It was then filtered and the filtrate concentrated. The residue waspurified by preparative. HPLC using CH₃CN—H₂O-TFA as solvent system.Homogeneous fractions were collected and concentrated in vacuo to givethe title compound as an orange colored solid, (9.1 mg, 0.015 mmol,21.26% yield). MS m/z 596 (MH⁺), Retention time: 2.893 min. (basic). 1HNMR (500 MHz, CHLOROFORM-D) δ ppm 1.06-2.28 (m, 19H) 2.47 (s, 3H)2.77-2.93 (m, 1H) 3.19 (s, 3H) 3.53-3.83 (s, br, 3H) 3.90 (s, 3H)4.58-4.73 (m, br, 1H) 4.86-5.03 (m, br, 1H) 6.71 (s, 1H) 6.92 (d, J=2.44Hz, 1H) 7.06 (dd, J=8.55, 2.75 Hz, 1H) 7.52 (d, J=8.54 Hz, 1H) 7.65 (dd,J=8.24, 1.22 Hz, 1H) 7.80-7.85 (m, 2H).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1,3-dimethyl-1H-pyrazol-5-yl]-

To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1,3-dimethyl-1H-pyrazol-5-yl]-,1,1-dimethylethyl ester (601 mg, 1.009 mmol) in 1,2-Dichloroethane (10mL), TFA (5 mL, 64.9 mmol) was added. The reaction mixture was stirredat RT for 4 hours. Solvent and TFA were then evaporated to give abrownish thick oil, (650 mg, 1.144 mmol, 113% yield). 10 mg of thiscrude product was purified by preparative HPLC using CH₃CN—H₂O-TFA assolvent system. Homogeneous fractions were combined and concentratedunder reduced pressure to give the title compound as a yellow solid,(3.5 mg, 35% recovery). MS m/z 540 (MH⁺), Retention time: 1.925 min.(basic). 1H NMR (500 MHz, MeOD) δ ppm 1.15-1.59 (m, 4H) 1.68-2.24 (m,6H) 2.41 (s, 3 H) 2.84-2.97 (m, 1H) 3.11-3.50 (m, br, 6H) 3.90 (s, 3H)4.55-4.69 (m, br, 1H) 4.94-5.06 (m, br, 1H) 6.88 (s, 1H) 7.07 (d, J=2.44Hz, 1H) 7.14 (dd, J=8.70, 2.59 Hz, 1H) 7.57 (d, J=8.55 Hz, 1H) 7.67 (dd,J=8.55, 1.22 Hz, 1H) 7.87 (d, J=8.54 Hz, 1H) 7.89 (s, 1H).

Note: The remaining crude product was used in the subsequent stepswithout further purification.

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-,methyl ester

To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1,3-dimethyl-1H-pyrazol-5-yl]-(225mg, 0.417 mmol) in tetrahydrofuran (10 mL), CDI (101 mg, 0.625 mmol) wasadded. The reaction mixture was heated at 60° C. for one hour and thenallowed to cool to RT. 2-Methylpropane-1-sulfonamide (172 mg, 1.251mmol) and DBU (0.126 mL, 0.834 mmol) were then added and the resultantmixture was heated at 60° C. for 4 hours. The reaction was then quenchedwith 1N HCl solution and the product extracted with ethyl acetate (2×40mL). The organic layers were combined, washed with 1N HCl solution,brine, dried (MgSO₄) and then filtered. Evaporation of the filtrate gavethe product as an orange colored oil. This material was then purified bypreparative HPLC using CH₃CN—H₂O-TFA as solvent system. Homogeneousfractions were combined and concentrated in vacuo, to provide the titlecompound as a yellow colored solid, (46.6 mg, 0.067 mmol, 16.12% yield).MS m/z 659 (MH⁺), Retention time: 2.197 min. (basic). 1H NMR (500 MHz,CHLOROFORM-D) δ ppm 1.14 (d, J=6.71 Hz, 6H) 1.19-1.60 (m, 4H) 1.70-2.15(m, 6H) 2.34-2.43 (m, 1H) 2.49 (s, 3H) 2.80-2.92 (m, 1H) 3.12-3.75 (m,8H) 3.91 (s, 3H) 4.63-4.74 (m, br, 1H) 4.85-4.99 (m, br, 1H) 6.75 (s,1H) 6.94 (d, J=2.75 Hz, 1H) 7.09 (dd, J=8.55, 2.75 Hz, 1H) 7.39 (dd,J=8.55, 1.53 Hz, 1H) 7.53 (d, J=8.55 Hz, 1H) 7.75 (d, J=1.22 Hz, 1H)7.90 (d, J=8.55 Hz, 1H) 8.52 (s, 1H).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl-1,3-dimethyl-,methyl ester

To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1,3-dimethyl-1H-pyrazol-5-yl]-(225mg, 0.417 mmol) in tetrahydrofuran (10 mL), CDI (101 mg, 0.625 mmol) wasadded. The reaction mixture was heated at 60° C. for one hour and wasthen allowed to cool to room temperature. Propane-2-sulfonamide (154 mg,1.251 mmol) and DBU (0.126 mL, 0.834 mmol) were then added and theresultant mixture was heated at 60° C. for 4 hours. The reaction wasthen quenched with 1N HCl solution and the product extracted with ethylacetate (2×40 mL). The organic layers were combined, washed with 1N HClsolution, brine, then dried (MgSO₄) and filtered. Evaporation ofsolvents gave the product as an orange colored thick oil. This materialwas then purified by preparative HPLC using CH₃CN—H₂O-TFA as solventsystem. Homogeneous fractions were combined and concentrated in vacuotoprovide the title compound as a yellow colored solid, (42.5 mg, 0.066mmol, 15.81% yield). MS m/z 645 (MH⁺), Retention time: 2.105 min.(basic). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.16-1.61 (m, 10H)1.69-2.21 (m, 6H) 2.48 (s, 3H) 2.81-2.92 (m, 1H) 3.24 (s, 3H) 3.66 (s,br, 3H) 3.91 (s, 3H) 4.01-4.10 (m, 1H) 4.63-4.75 (m, br, 1H) 4.84-4.98(m, br, 1H) 6.74 (s, 1H) 6.94 (d, J=2.75 Hz, 1H) 7.08 (dd, J=8.55, 2.75Hz, 1H) 7.39 (dd, J=8.55, 1.22 Hz, 1H) 7.53 (d, J=8.55 Hz, 1H) 7.74 (d,J=1.22 Hz, 1H) 7.90 (d, J=8.55 Hz, 1H) 8.28 (s, 1H).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-,methyl ester

To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1,3-dimethyl-1H-pyrazol-5-yl]-(120mg, 0.222 mmol) in THF (5 mL), CDI (54.1 mg, 0.334 mmol) was added. Thereaction mixture was heated at 60° C. for one hour, and then allowed tocool to room temperature. N,N-dimethylsulfamide (83 mg, 0.667 mmol) andDBU (0.067 mL, 0.445 mmol) were then added and the resultant mixture washeated at 60° C. overnight. The reaction was then quenched with 1N HClsolution and the product extracted with ethyl acetate (2×30 mL). Theorganic layers were combined, washed with 1N HCl solution, brine, dried(MgSO₄) and then filtered. Evaporation of solvents gave the curdeproduct as an orange colored thick oil. This material was then purifiedby preparative HPLC using CH₃CN—H₂O-TFA as a solvent system. Homogeneousfractions were combined and concentrated under vacuum to provide thetitle compound as an orange colored solid, (31.4 mg, 0.049 mmol, 21.87%yield). MS m/z 646 (MH⁺), Retention time: 2.245 min. (basic). 1H NMR(500 MHz, CHLOROFORM-D) δ ppm 1.18-1.60 (m, 4H) 1.70-2.14 (m, 6H) 2.49(s, 3H) 2.80-2.91 (m, 1H) 3.05 (s, 6H) 3.24 (s, 3H) 3.68 (s, br, 3H)3.91 (s, 3 H) 4.64-4.74 (m, br, 1H) 4.86-5.00 (m, br, 1H) 6.74 (s, 1H)6.94 (d, J=2.75 Hz, 1H) 7.08 (dd, J=8.85, 2.75 Hz, 1H) 7.35 (dd, J=8.55,1.53 Hz, 1H) 7.53 (d, J=8.55 Hz, 1H) 7.75 (d, J=1.22 Hz, 1H) 7.89 (d,J=8.54 Hz, 1H) 8.44 (s, 1H).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-,methyl ester (44.2 mg, 0.067 mmol) in tetrahydrofuran (2.0 mL) and MeOH(2.000 mL), 1N NaOH (0.537 mL, 0.537 mmol) solution was added. Thereaction mixture was stirred at RT for 4 days. LC/MS showed that only˜25% of the starting ester was hydrolyzed. 0.5 mL of more 1N NaOHsolution was added. The reaction mixture was then stirred at RT forthree more days. The reaction mixture was concentrated, and the residuewas acidified using 1N HCl solution. The resultant mixture was thenextracted with ethyl acetate (2×20 mL) and the organic layers werecombined, washed with brine, dried (MgSO₄) and then filtered.Evaporation of filtrate gave the crude product as a viscousorange-colored oil. This material was then purified by preparative HPLCusing CH₃CH—H₂O-TFA as a solvent system. Homogeneous fractions werecollected concentrated under reduced pressure to give the title compoundas a light yellow colored solid, (12.2 mg, 0.019 mmol, 28.2% yield). MSm/z 645 (MH⁺), Retention time: 1.847 min. (basic). 1H NMR (500 MHz,DMSO-D6) δ ppm 1.02 (d, J=6.71 Hz, 6H) 1.08-1.53 (m, 4H) 1.64-2.09 (m,6H) 2.08-2.20 (m, 1H) 2.36 (s, 3H) 2.71-2.85 (m, 1H) 3.09 (s, 3H) 3.45(d, J=6.71 Hz, 2H) 3.88 (s, 3H) 4.42-4.62 (m, br, 1H) 4.96-5.18 (m, br,1H) 6.97 (s, 1H) 7.15 (d, J=2.75 Hz, 1H) 7.21 (dd, J=8.85, 2.75 Hz, 1H)7.54 (d, J=8.85 Hz, 1H) 7.60 (dd, J=8.39, 1.37 Hz, 1H) 7.90 (d, J=8.54Hz, 1H) 8.14 (s, 1H) 11.76 (s, 1H) 12.37 (s, br, 1H).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-,methyl ester (29.4 mg, 0.046 mmol) in THF (1.5 mL) and MeOH (1.500 mL),1N NaOH (0.364 mL, 0.364 mmol) solution was added. The reaction mixturewas stirred at RT for 4 days. LC/MS showed that only ˜40% ester washydrolyzed. 0.5 mL of more 1N NaOH solution was added. The reactionmixture was then stirred at RT for three more days. The reaction mixturewas concentrated and the residue acidified using 1N HCl solution. Theproduct was then extracted with ethyl acetate (2×20 mL). The organiclayers were combined, washed with brine, dried (MgSO₄) and thenfiltered. Evaporation of filtrate gave the crude product as an orangecolored oil. This material was then purified by preparative HPLC usingCH₃CN—H₂O-TFA as a solvent system. Homogeneous fractions were combinedand concentrated in vacuo to give the title compound as a light yellowcolored solid, (9.5 mg, 0.015 mmol, 33.0% yield). MS m/z 632 (MH⁺),Retention time: 1.853 min. (basic). 1H NMR (500 MHz, DMSO-D6) δ ppm1.06-1.53 (m, 4H) 1.58-2.07 (m, 6H) 2.35 (s, 3H) 2.74-2.83 (m, 1H) 2.87(s, 6H) 3.02-3.16 (s, br, 3H) 3.88 (s, 3H) 4.41-4.61 (m, br, 1H)4.96-5.20 (m, br, 1H) 6.97 (s, 1H) 7.15 (d, J=2.75 Hz, 1H) 7.20 (dd,J=8.55, 2.75 Hz, 1H) 7.54 (d, J=8.55 Hz, 1H) 7.60 (dd, J=8.55, 1.53 Hz,1H) 7.89 (d, J=8.54 Hz, 1H) 8.14 (s, 1H) 11.51 (s, 1H) 12.35 (s, br,1H).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-

To a mixture of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-,methyl ester (80 mg, 0.124 mmol) and potassium trimethylsilanolate(TMSOK) (31.8 mg, 0.248 mmol) in a round-bottomed flask, Tetrahydrofuran(8 mL) was added. The resultant mixture was then stirred at RTovernight. LC/MS showed that only 40% of SM reacted. Two moreequivalents of TMSOK were added and stirring was continued for 48 hrs.The reaction mixture was then concentrated and 1N HCl solution wasadded. A yellow solid separated (85 mg). and 10 mg of the material wasthen purified by preparative HPLC using CH₃CN—H₂O-TFA as solvent system.Homogeneous fractions were combined and evaporated under vacuum to givethe title compound as a yellow colored solid, (7.6 mg, 76% recovery). MSm/z 631 (MH⁺), Retention time: 1.648 min. (basic). 1H NMR (500 MHz,Acetone) δ ppm 1.11-1.61 (m, 10H) 1.63-2.21 (m, 6H) 2.38 (s, 3H)2.85-3.00 (m, 1H) 3.17 (s, 3 H) 3.83-3.97 (m, 4H) 4.54-4.72 (m, br, 1H)5.09-5.29 (m, br, 1H) 6.93 (s, 1H) 7.11 (d, J=2.75 Hz, 1H) 7.17 (dd,J=8.55, 2.75 Hz, 1H) 7.61 (d, J=8.55 Hz, 1 H) 7.68 (dd, J=8.55, 1.53 Hz,1H) 7.96 (d, J=8.55 Hz, 1H) 8.21 (s, 1H) 9.96 (s, 1H). Note: The crudeproduct describe above can be used without further purification for thepreparation of carboxamide examples of the current invention.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[1,3-dimethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-(9.5mg, 0.015 mmol) in DMSO (1 mL), TBTU (9.66 mg, 0.030 mmol) and DIPEA(0.013 mL, 0.075 mmol) were added. The reaction mixture was stirred atRT for 15 min. Morpholine (1.965 mg, 0.023 mmol) was then added and theresultant solution was stirred at RT for 48 hours. The reaction mixturewas then purified by preparative HPLC using CH₃CN—H₂O-TFA as a solventsystem. Homogeneous fractions were combined and concentrated undervacuum. The title compound was obtained as a yellow colored solid, (8.0mg, 0.011 mmol, 74.4% yield). MS m/z 699 (M−H⁻), Retention time: 1.990min. (basic). 1H NMR (500 MHz, MeOD) δ ppm 1.18-1.64 (m, 4H) 1.73-2.26(m, 9H) 2.59-3.09 (m, 15H) 3.85 (s, 3H) 3.95 (s, 3H) 4.67 (d, J=14.96Hz, 1H) 5.02-5.15 (m, 1H) 7.07 (s, 1H) 7.15 (d, J=2.44 Hz, 1H) 7.20 (dd,J=8.55, 2.75 Hz, 1H) 7.56-7.64 (m, 2H) 7.92 (s, 1H) 7.98 (d, J=8.55 Hz,1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1,3-dimethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-(10mg, 0.016 mmol) in DMSO (1 mL), TBTU (9.96 mg, 0.031 mmol) and DIPEA(0.014 mL, 0.078 mmol) were added. The reaction mixture was stirred atRT for 15 min. Morpholine (1.351 mg, 0.016 mmol) was then added and theresultant solution was stirred at RT overnight. The reaction mixture wasthen purified by preparative HPLC using CH₃CN—H₂O-TFA as a solventsystem. Homogeneous fractions were collected and concentrated undervacuum, to provide the title compound as a yellow colored solid, (10.7mg, 0.015 mmol, 95% yield). MS m/z 712 (M−H⁻), Retention time: 1.895min. (basic). 1H NMR (500 MHz, MeOD) δ ppm 1.16 (d, J=6.71 Hz, 6H)1.20-1.64 (m, 4H) 1.73-2.27 (m, 9H) 2.29-2.43 (m, 1H) 2.56-3.14 (m, 9H)3.49-3.55 (m, 2H) 3.85 (s, 3H) 3.95 (s, 3H) 4.67 (d, J=14.96 Hz, 1H)4.98-5.16 (m, br, 1H) 7.07 (s, 1H) 7.15 (d, J=2.44 Hz, 1H) 7.20 (dd,J=8.70, 2.59 Hz, 1H) 7.55-7.66 (m, 2H) 7.95 (s, 1H) 7.98 (d, J=8.55 Hz,1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1,3-dimethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-(20mg, 0.032 mmol) in DMSO (1 mL), TBTU (20.36 mg, 0.063 mmol) and DIPEA(0.028 mL, 0.159 mmol) were added. The reaction mixture was stirred atRT for 15 min. Morpholine (4.14 mg, 0.048 mmol) was then added and theresultant solution was stirred at RT overnight. The reaction mixture wasthen purified by preparative HPLC using CH₃CN—H₂O-TFA as a solventsystem. Homogeneous fractions were combined and concentrated undervacuum. The title compound was obtained as a yellow colored solid, (16.8mg, 0.024 mmol, 74.2% yield). MS m/z 698 (M−H⁻), Retention time: 1.798min. (basic). 1H NMR (500 MHz, MeOD) δ ppm 1.18-1.62 (m, 10H) 1.72-2.25(m, 9H) 2.53-3.23 (m, 9H) 3.84 (s, 3H) 3.95 (s, 3H) 3.96-4.03 (m, 1H)4.64 (d, J=14.95 Hz, 1H) 5.00-5.15 (m, br, 1H) 7.06 (s, 1H) 7.14 (d,J=2.44 Hz, 1H) 7.19 (dd, J=8.55, 2.75 Hz, 1H) 7.55-7.65 (m, 2H) 7.94 (s,1H) 7.98 (d, J=8.55 Hz, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1,3-dimethyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-(20mg, 0.032 mmol) in DMSO (1 mL), TBTU (20.36 mg, 0.063 mmol) and DIPEA(0.028 mL, 0.159 mmol) were added. The reaction mixture was stirred atRT for 15 min. Then 3-methyl-3,8-diazabicyclo[3.2.1]octane.2 HCl (9.47mg, 0.048 mmol) was added. The solution was then stirred at RTovernight. The crude reaction mixture was then purified by preparativeHPLCusing CH₃CN—H₂O-TFA as solvent system. Homogeneous fractions werecombined and concentrated under vacuum to afford the title compound as ayellow solid, (19.7 mg, 0.023 mmol, 71.4% yield) as TFA salt. MS m/z 737(M−H⁻), Retention time: 2.040 min. (basic). 1H NMR (500 MHz, MeOD) δ ppm1.16-1.67 (m, 14H) 1.74-2.25 (m, 6H) 2.38 (s, 3H) 2.51-2.66 (m, 1H) 2.72(s, 3H) 2.94-3.05 (m, 1H) 3.16-3.39 (m, 5H) 3.84 (s, 3H) 3.96 (s, 3H)3.98-4.05 (m, 1H) 4.59-4.71 (m, br, 1H) 4.94-5.05 (m, br, 1H) 7.14-7.28(m, 3H) 7.62-7.66 (m, 2H) 7.91 (s, 1H) 8.00 (d, J=8.54 Hz, 1 H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1,3-dimethyl-4-[[cis-2,6-dimethyl-4-morpholinyl]carbonyl]-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-(13mg, 0.021 mmol) in DMSO (1 mL), TBTU (13.24 mg, 0.041 mmol) and DIPEA(0.018 mL, 0.103 mmol) were added. The reaction mixture was stirred atRT for 15 min. Then cis-2,6-dimethylmorpholine (3.56 mg, 0.048 mmol) wasadded and the resultant mixture was stirred at RT overnight. The crudereaction mixture was purified by preparative HPLC using CH₃CN—H₂O-TFA asa solvent system. Homogeneous fractions were combined and concentratedunder vacuum to afford the title compound as a yellow colored solid,(10.1 mg, 0.014 mmol, 67.3% yield). MS m/z 326 (M−H⁻), Retention time:1.958 min. (basic). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.57-2.33 (m,25H) 2.81-3.60 (m, 5H) 3.77-3.99 (m, 8H) 4.03-4.12 (m, 1H) 4.57 (d,J=15.26 Hz, 1H) 4.76-4.94 (m, 1H) 6.75-6.88 (m, 1H) 6.95 (s, 1H) 7.12(dd, J=8.55, 2.14 Hz, 1H) 7.50-7.67 (m, 2H) 7.71 (s, 1H) 7.91 (d, J=8.24Hz, 1 H).

Methyl 1-(1-methylethyl)-3-methyl-1H-pyrazole-4-carboxylate

To a solution of 1-(1-methylethyl)-3-methyl-1H-pyrazole-4-carboxyllicacid (2.00 g, 11.9 mmol) in benzene (15.9 mL) and methanol (7.93 mL) atroom temperature was added 2M trimethylsilyldiazomethane (23.8 mL). Theresulting solution was stirred at room temperature for 3 hours. Solventwas removed at reduced pressure on a rotory evaporator to yield thetitle compound (2.17 g, 11.89 mmol, 100% yield) as a white solid.

MS m/z 183 (MH⁺)

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.49 (d, 6H) 2.48 (s, 3H) 3.81 (s,3 H) 4.42 (m, 1H) 7.86 (s, 1H).

Methyl 5-iodo-1-(1-methylethyl)-3-methyl-1H-pyrazole-4-carboxylate

To a solution of methyl1-(1-methylethyl)-3-methyl-1H-pyrazole-4-carboxylate (2.00 g, 11.0 mmol)in dry tetrahydrofuran (22.0 mL) at −78° C., 2 M solution ofbutyllithium (6.04 mL, 12.1 mmol) in pentane was added dropwise. Thereaction mixture was then warmed to −45° C. and stirred for 1 h. It wasthen cooled to −78° C. and a solution of iodine (3.06 g, 12.1 mmol) inTHF (11.0 mL) was added. The reaction mixture was warmed to RT andstirred for 1 h. Then it was quenched with saturated NH₄Cl solution andextracted with ethyl acetate (2×25 mL). The organic layers werecombined, washed with brine and dried (MgSO₄). Evaporation of solventgave a tan solid as title compound (3.38 g, 11.0 mmol, 100% crudeyield). MS m/z 309 (MH⁺); 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.41 (d,6H) 2.47 (s, 3H) 3.82 (s, 3H) 4.77 (m, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1-(1-methylethyl)-3-methyl-1H-pyrazol-5-yl]-,1,1-dimethylethyl ester

In a microwave tube, 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester(611 mg, 0.834 mmol), methyl5-iodo-1-(1-methylethyl)-3-methyl-1H-pyrazole-4-carboxylate (360 mg,1.17 mmol) and bis(triphenylphosphine)palladium II chloride (58.5 mg,0.083 mmol) were added. It was then sealed, degassed and flushed withnitrogen. 1,4-Dioxane (4.17 mL) was added. The reaction mixture washeated at 160° C. under microwave condition for 1 hour. It was thenfiltered and the filtrate was concentrated. The residue was purified ona Shimadzu high pressure liquid chromatography system employingDiscovery VP software interfaced with a SCL-10A controller, SIL-10Aautosampler and FRC-10A fraction collector. The sample was dissolved inacetonitrile/DMF (1:1) (8 ml) purified using a Waters Sunfire Prep C18OBD, 5 uM 19 mm×100 mm column and monitored using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 25 mL/min, a gradient of 25% solvent A/75%solvent B to 0% solvent A/100% solvent B, a gradient time of 10 minuteswith a run time of 20 minutes using % A=10% acetonitrile, 90% water,0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA solvent system.

The product-containing fractions were collected and concentrated to givetitle compound as a yellow solid (156 mg, 0.250 mmol, 30% yield).

MS m/z 624 (MH⁺); 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.41 (br s, 3H)1.18-1.59 (m, 16H) 1.72-2.20 (m, 6H) 2.49 (s, 3H) 2.86 (m, 1H) 3.68 (m,1H) 3.85 (br s, 3H) 3.92 (s, 3H) 4.69 (br.d, 1H) 4.97 (br.d, 1H) 6.68(s, 1H) 6.92 (d, J=2.14 Hz, 1H) 7.06 (dd, J=8.55, 2.44 Hz, 1H) 7.51 (d,J=8.55 Hz 1H) 7.73 (d, J=8.24 Hz, 1H) 7.81 (d, J=8.24 Hz, 1H) 7.87 (s,1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1(1-methylethyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-

To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1-(1-methylethyl)-3-methyl-1H-pyrazol-5-yl]-,1,1-dimethylethyl ester (156 mg, 0.250 mmol) in 1,2-dichloroethane (4mL), TFA (4 mL) was added. The reaction mixture was stirred at RT for 2hours. Volatiles were removed on a rotary evaporator to give the titlecompound as a brownish thick oil as crude product (142 mg, 0.8250 mmol,100% yield).

MS m/z 568 (MH⁺)

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.41 (br s, 3H) 1.18-1.59 (m, 7H)1.72-2.20 (m, 6H) 2.52 (s, 3H) 2.87 (m, 1H) 3.63 (m, 1H) 3.85 (br s, 3H) 3.91 (s, 3H) 4.71 (br.d, 1H) 4.96 (br.d, 1H) 6.68 (s, 1H) 6.96 (d,J=2.14 Hz, 1H) 7.08 (dd, J=8.55, 2.44 Hz, 1H) 7.52 (d, J=8.55 Hz 1H)7.77 (d, J=8.24 Hz, 1H) 7.87 (d, J=8.24 Hz, 1H) 7.97 (s, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1(1-methylethyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-

To a solution of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1(1-methylethyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-(110mg, 0.194 mmol) in tetrahydrofuran (0.646 mL) was addedcarbonyldiimidazole (94.0 mg, 0.581 mmol). The reaction mixture washeated at 60° C. for one hour. Propane-2-sulfonamide (95 mg, 0.775 mmol)and DBU (0.088 mL, 0.581 mmol) were added at room temperature. Thereaction mixture was then heated at 60° C. for 4 hours. The reactionmixture was diluted with 1N HCl (50 mL) solution and extracted withethyl acetate (2×40 mL). The organic layers were combined andconcentrated on a rotory evaporator to give an orange oil as crudeproduct. It was then purified by prep HPLC column using CH₃CN/H₂O/TFA assolvent system. Fractions were collected and concentrated under speedvacfor 16 h. A yellow solid was obtained as title compound (114 mg, 0.169mmol, 87% yield).

MS m/z 673 (MH⁺).

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.41 (br s, 3H) 1.18-1.52 (m, 13 H)1.70-2.20 (m, 6H) 2.51 (s, 3H) 2.85 (m, 1H) 3.59 (m, 1H) 3.87 (s, 3H)3.92 (s, 3H) 4.02 (m, 1H) 4.73 (br.d, 1H) 4.97 (br.d, 1H) 6.67 (s, 1H)6.96 (d, J=2.14 Hz, 1H) 7.08 (dd, J=8.55, 2.44 Hz, 1H) 7.40-7.62 (m, 2H)7.78-7.84 (m, 2H), 9.00 (br s, 1H).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(1-methylethyl)-3-methyl-

To a mixture of 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1(1-methylethyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-(110mg, 0.163 mmol) was dissolved in THF (0.272 mL) and methanol (0.272 mL)was added to the reaction followed by 1N aqueous sodium hydroxide (0.600mL). The reaction was capped under a nitrogen atmosphere and stirred atroom temperature for 18 hrs. The reaction was diluted with ethyl acetate(25.0 mL) and washed with 10N aqueous hydrochloric acid (2×20 ml). Theorganic layer was concentrated in vacuuo using a rotary evaporator toyield the title compound as a yellow solid (107 mg, 0.163 mmol, 100%).

MS m/z 659 (MH⁺)

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.39 (br s, 3H) 1.18-1.52 (m, 13 H)1.70-2.20 (m, 6H) 2.48 (s, 3H) 2.83 (m, 1H) 3.51 (m, 1H) 3.87 (s, 3H)4.02 (m, 1H) 4.72 (br.d, 1H) 4.98 (br.d, 1H) 6.65 (s, 1H) 6.95 (d,J=2.14 Hz, 1H) 7.08 (dd, J=8.55, 2.44 Hz, 1H) 7.41-7.60 (m, 2H)7.79-7.83 (m, 2H), 8.96 (br s, 1 H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[3-methyl-1-(1-methylethyl)-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-

To a solution of 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(1-methylethyl)-3-methyl-(25mg, 0.038 mmol) in DMSO (0.38 mL), TBTU (24 mg, 0.076 mmol) and DIPEA(0.020 mg, 0.44 mmol) were added. The reaction mixture was stirred at RTfor 15 min. Then morpholine (38 mg, 0.15 mmol) was added. The solutionwas stirred at RT for overnight. The reaction mixture was purified byprep HPLC column using CH₃CN/H₂O/TFA as solvent system. Fractions werecollected and concentrated under speedvac overnight to yield the titlecompound as a yellow solid (24 mg, 0.031 mmol, 81% yield).

MS m/z 728 (M−H⁺)

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.18-1.70 (m, 16H) 1.75-2.16 (m,6H) 2.30 (s, 3H) 2.60-3.31 (m, 9H) 3.94 (m, 3H) 4.04 (m, 1H) 4.56 (br.m,2 H) 4.93 (br.d, 1H) 6.79 (br s, 1H) 6.94 (s, 1H) 7.12 (dd, J=8.55, 2.44Hz, 1H) 7.57 (d, J=8.55 Hz 1H) 7.66 (br s, 1H) 7.82 (s, 1H) 7.97 (d,J=8.55 Hz, 1H), 10.20 (br s, 1H).

The following compounds were synthesized by an analogous method asdescribed above for 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[3-methyl-1-(1-methylethyl)-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-:

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

MS m/z 756 (M−H⁺)

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.70-0.91 (br m, 6H) 1.02-1.81 (m,16H) 1.86-2.16 (m, 6H) 2.28 (s, 3H) 2.85-3.29 (m, 5H) 3.96 (s, 3H) 4.12(br m, 3H) 4.55 (br.m, 2H) 4.92 (br.d, 1H) 6.73 (br s, 1H) 6.94 (br s,1H) 7.16 (dd, J=8.55, 2.44 Hz, 1H) 7.51-7.72 (m, 2H) 7.76-7.98 (m, 2H),10.50 (br s, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[3-methyl-1-(1-methylethyl)-4-[(4-methyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-

MS m/z 741 (M−H⁺)

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.15-1.81 (m, 18H) 1.86-2.12 (m,4H) 2.21-2.45 (m, 5H) 2.61-3.05 (m, 6H) 3.10-3.75 (m, 4H) 3.93 (s, 3H)4.04 (m, 1H) 4.61 (br.m, 2H) 4.90 (br.d, 1H) 6.86 (br s, 1H) 6.96 (s,1H) 7.14 (br m, 1H) 7.59-7.83 (m, 3H) 7.93 (br s, 1H), 10.10 (br s, 1H).

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[3-methyl-1-(1-methylethyl)-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-

MS m/z 769 (M−H⁺)

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.21 (br s, 1H) 1.02 (br s, 3H)1.15-1.60 (m, 17H) 1.69-2.12 (m, 8H) 2.28 (m, 4H) 2.69-3.60 (m, 6H) 3.96(s, 3 H) 4.08 (br m, 3H) 4.60 (br.m, 2H) 4.88 (br.m, 1H) 6.82 (br s, 1H)6.95 (s, 1H) 7.15 (br m, 1H) 7.55-7.74 (m, 2H) 7.78-7.99 (m, 2H), 10.12(br s, 1H).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-

Dissolve 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-,ethyl ester (1.044 g, 1.619 mmol) in a pre-mixed solution of THF (20mL), MeOH (20 mL) and sodium hydroxide (20 mL, 20.00 mmol). The reactionwas homogenous and was stirred at room temperature under a nitrogenatmosphere for 26 hrs then concentrated in vacuuo using a rotaryevaporator with a bath temperature at 20 C. The reaction was poured into1N aqueous hydrochloric acid and extract using ethyl acetate. Thecombined organic layers were washed sequentially with 1N aqueoushydrochloric acid and brine, then dried over magnesium sulfate, filteredand solvent removed in vacuuo. The crude product dried in vacuuo at roomtemperature to yield 1.68 g of an orange amorphous solid. The crudeproduct was dissolved in chloroform (approximately 50 mL) with heatingand hexanes were added until some material starts to precipitate butre-dissolves on swirling (approximately 10-12 ml of hexanes). Themixture was allowed to slowly cool to room temperature and then allowedto stand at room temperature for a few hours. The very fine particulateyellow precipitate was filtered using a Buchner funnel and dried invacuuo at room temperature to yield 819 mg (45%) of purified product asa bright yellow amorphous solid. The title compound 4.6 mg was dissolvedin CDCl3 (2 ml) with the addition of approximately 5 drops of CD3OD toaid in dissolution for 1H NMR acquisition.

1H NMR (500 MHz, CHLOROFORM-D/CD3OD) δ ppm 1.11-1.39 (m, 3 H) 1.41 (d,J=7.02 Hz, 6H) 1.47-1.65 (m, 1H) 1.75 (d, J=8.85 Hz, 2H) 1.82-2.27 (m,13H) 2.77-2.90 (m, 1H) 3.28 (s, 3H) 3.88 (s, 3H) 3.97-4.06 (m, 1H) 4.66(s, 1H) 5.01 (s, 1H) 6.76 (s, 1H) 6.92 (d, J=2.75 Hz, 1H) 7.04 (dd,J=8.70, 2.59 Hz, 1H) 7.47-7.54 (m, 2H) 7.81 (d, J=1.22 Hz, 1H) 7.86 (d,J=8.54 Hz, 1H) 7.91 (s, 1 H).

LC-MS retention time 1.39 min; 615 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-

In a 2 dram vial, 900 uL of a stock solution containing

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(0.09M,0.081 mmol) and TBTU (0.19M, 0.171 mmol) in DMF was stirred under anitrogen atmosphere for 1 hour at room temperature. DMAP (40 mg, 0.327mmol) was added to the reaction and stirred until dissolved then theamine reagent, 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride(35 mg, 0.176 mmol), was added and the reaction capped under nitrogenand stirred at room temperature overnight. The reaction was diluted withethyl acetate and washed sequentially with 1.0N aqueous hydrochloricacid and brine. The organic phase was dried over MgSO4, filtered andsolvent removed in vacuuo. The crude product was dried in vacuuo at roomtemperature to yield 63 mg of an amorphous yellow film/foam. The samplewas purified on a Shimadzu high pressure liquid chromatography systememploying Discovery VP software interfaced with a SCL-10A controller,SIL-10A autosampler and FRC-10A fraction collector. The sample wasdissolved in acetonitrile/DMF (1:1) (2 mL) purified using a WatersSunfire Prep C18 OBD, 5 uM 19 mm×100 mm column and monitored using aSPD-10AV UV-Vis detector at a detector wave length of 220 nM. Theelution conditions employed a flow rate of 25 mL/min, a gradient of 70solvent A/30% solvent B to 0% solvent A/100% solvent B, a gradient timeof 15 minutes with a run time of 20 minutes using % A=10% acetonitrile,90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA solventsystem. Sample was purified in two HPLC injections, and the productfractions combined (retention time=5.5 min) and volatiles removed invacuuo. The sample was dried in vacuuo at room temperature to yield 44.4mg of the title compound as a TFA salt.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.10-1.31 (m, 1H) 1.33-1.57 (m,10H) 1.80 (s, 2H) 1.89-2.16 (m, 5H) 2.57 (s, 4H) 2.74 (s, 9H) 2.84-3.12(m, 4H) 3.27 (s, 2H) 3.32-3.72 (m, 4H) 3.88 (s, 3H) 3.94 (s, 4H)4.00-4.14 (m, 1H) 4.63 (d, J=15.56 Hz, 1H) 4.89 (d, J=12.21 Hz, 1H) 6.96(d, J=2.14 Hz, 2 H) 7.13 (dd, J=8.55, 2.44 Hz, 1H) 7.57 (d, J=8.85 Hz,1H) 7.63 (d, J=7.63 Hz, 2H) 7.76 (s, 1H) 7.93 (d, J=8.55 Hz, 1H).

LC-MS retention time 1.81 min; 723 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[3-(dimethylamino)-1-piperidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

In a 2 dram vial, 900 uL of a stock solution containing

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(0.09M,0.081 mmol) and TBTU (0.19M, 0.171 mmol) in DMF was stirred under anitrogen atmosphere for 1 hour at room temperature. DMAP (42 mg, 0.344mmol) was added to the reaction and stirred until dissolved then theamine reagent, N,N-dimethylpiperidin-3-amine dihydrochloride (34 mg,0.169 mmol) was added and the reaction capped under nitrogen and stirredat room temperature overnight. The reaction was diluted with ethylacetate and washed sequentially with 1.0N aqueous hydrochloric acid andbrine. The organic phase was dried over MgSO4, filtered and solventremoved in vacuuo. The crude product was dried in vacuuo at roomtemperature to yield 67 mg as a yellow film. The sample was purified ona Shimadzu high pressure liquid chromatography system employingDiscovery VP software interfaced with a SCL-10A controller, SIL-10Aautosampler and FRC-10A fraction collector. The sample was dissolved inacetonitrile/DMF (1:1) (2 mL) purified using a Waters Sunfire Prep C18OBD, 5 uM 19 mm×100 mm column and monitored using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 25 mL/min, a gradient of 70 solvent A/30%solvent B to 0% solvent A/100% solvent B, a gradient time of 15 minuteswith a run time of 20 minutes using % A=10% acetonitrile, 90% water,0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA

Combine product fractions, retention time=5.03 min, remove volatiles invacuuo and dry at room temperature in vacuuo to yield 26.2 mg of thetitle compound as an amorphous yellow solid.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.04-1.18 (m, 1H) 1.18-1.45 (m, 6H)1.48 (d, J=6.71 Hz, 7H) 1.80 (d, J=8.55 Hz, 3H) 1.86-2.26 (m, 5H)2.37-2.99 (m, 20H) 3.12-3.72 (m, 4H) 3.85 (s, 4H) 3.93 (s, 3H) 3.98-4.08(m, 1H) 4.23 (s, 0.4H) 4.60 (d, J=14.34 Hz, 1H) 4.86 (d, J=11.90 Hz, 1H)6.82-7.02 (m, 2H) 7.11 (d, J=7.02 Hz, 1H) 7.53 (d, J=8.55 Hz, 1H)7.58-7.88 (m, 3 H) 7.94 (d, J=8.24 Hz, 1H) 10.05 (s, 0.6H)

LC-MS retention time 1.54 min; 725 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

13-cyclohexyl-6-(4-(((2R,6S)-2,6-dimethyl-4-morpholinyl)carbonyl)-1-methyl-1H-pyrazol-5-yl)-N-(isopropylsulfonyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxamide

In a 2 dram vial, 932 uL of a stock solution containing

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(0.087M,0.081 mmol) and TBTU (0.18M, 0.168 mmol), in DMF was stirred under anitrogen atmosphere for 1.75 hours at room temperature. DMAP (40 mg,0.327 mmol) was added to the reaction and stirred until dissolved thenthe amine reagent, (2R,6S)-2,6-dimethylmorpholine (0.030 mL, 0.243mmol), was added and the reaction capped under nitrogen and stirred atroom temperature overnight (19 hrs). The reaction was diluted with ethylacetate and washed sequentially with 1.0N aqueous hydrochloric acid andbrine. The organic phase was dried over MgSO4, filtered and solventremoved in vacuuo. The crude product was dried in vacuuo at roomtemperature to yield 65 mg of a yellow film. The sample was purified ona Shimadzu high pressure liquid chromatography system employingDiscovery VP software interfaced with a SCL-10A controller, SIL-10Aautosampler and FRC-10A fraction collector. The sample was dissolved inacetonitrile/DMF (1:1) (2 mL) purified using a Waters Sunfire Prep C18OBD, 5 uM 19 mm×100 mm column and monitored using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 25 mL/min, a gradient of 70 solvent A/30%solvent B to 0% solvent A/100% solvent B, a gradient time of 15 minuteswith a run time of 25 minutes using % A=10% acetonitrile, 90% water,0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA Retention time ofproduct=12.83 minutes. The sample was purified in two 1 ml injections,the second run was cut to a runtime of 20 minutes with the same 15 mingradient. Combine product fractions and remove volatiles in vacuuo usinga rotary evaporator then dry sample in vacuuo at room temperature toyield 26.1 mg of the title compound as an opaque yellow solid/amorphousfilm.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.60-0.93 (m, 6H) 1.16-1.29 (m, 2H)1.30-1.58 (m, 9H) 1.79 (d, J=10.68 Hz, 2H) 1.92 (s, 14H) 2.05-2.27 (m,3H) 2.88 (t, J=11.44 Hz, 1H) 3.13-3.31 (m, 2H) 3.46 (br.s, 1H) 3.91 (s,3 H) 3.94 (s, 3H) 4.02-4.13 (m, 1H) 4.60 (d, J=15.56 Hz, 1H) 4.90 (d,J=15.56 Hz, 1H) 6.83 (br. s, 1H) 6.95 (d, J=2.14 Hz, 1H) 7.06-7.17 (m,1H) 7.49-7.80 (m, 4 H) 7.93 (s, 1H) 10.12 (br.s, 0.2H) 10.47 (br.s,0.6H).

LC-MS retention time 1.90 min; 712 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

13-cyclohexyl-6-(4-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-5-yl)-N-(isopropylsulfonyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxamide

In a 2 dram vial, 932 uL of a stock solution containing

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(0.087M,0.081 mmol) and TBTU (0.18M, 0.168 mmol), in DMF was stirred under anitrogen atmosphere for 1.75 hours at room temperature. DMAP (41.8 mg,0.342 mmol) was added to the reaction and stirred until dissolved thenthe amine reagent, dimethylamine hydrochloride (17.5 mg, 0.215 mmol),was added and the reaction capped under nitrogen and stirred at roomtemperature overnight (19 hrs). The reaction was diluted with ethylacetate and washed sequentially with 1.0N aqueous hydrochloric acid andbrine. The organic phase was dried over MgSO4, filtered and solventremoved in vacuuo. The crude product was dried in vacuuo at roomtemperature to yield 57 mg as a yellow foam/amorphous solid/film.

The sample was purified on a Shimadzu high pressure liquidchromatography system employing Discovery VP software interfaced with aSCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector.The sample was dissolved in acetonitrile/DMF (1:1) (2 mL) purified usinga Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column and monitoredusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 25 mL/min, a gradient of70 solvent A/30% solvent B to 0% solvent A/100% solvent B, a gradienttime of 15 minutes with a run time of 20 minutes using % A=10%acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1%TFA Retention time of product=12.05 minutes. The sample was purified intwo 1 ml injections. Combine product fractions and remove volatiles invacuuo using a rotary evaporator then dry sample in vacuuo at roomtemperature to yield 37.6 mg (68%) as an amorphous yellow solid.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.15-1.30 (m, 1H) 1.33-1.45 (m, 2H)1.49 (br.s, 7H) 1.79 (d, J=8.55 Hz, 2H) 1.91-2.17 (m, 7H) 2.32 (br.s,9H) 2.45 (br.s, 3H) 2.78-2.91 (m, 1H) 3.50 (br.s, 1H) 3.82 (s, 3H) 3.93(s, 3 H) 4.01-4.10 (m, 1H) 4.60 (d, J=14.34 Hz, 1H) 4.93 (d, J=14.65 Hz,1H) 6.86 (s, 1H) 6.96 (d, J=2.75 Hz, 1H) 7.10 (dd, J=8.70, 2.59 Hz, 1H)7.53 (d, J=8.55 Hz, 1H) 7.58 (d, J=8.55 Hz, 1H) 7.66 (s, 1H) 7.75 (s,1H) 7.91 (d, J=8.55 Hz, 1H) 9.99 (br.s, 1H).

LC-MS retention time 1.74 min; 642 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[[(1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl]carbonyl]-1H-pyrazol-5-yl]-

In a 2 dram vial, 900 uL of a stock solution containing1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(0.09M,0.081 mmol) and TBTU (0.19M, 0.171 mmol) in DMF was stirred under anitrogen atmosphere for 1 hour at room temperature. DMAP (41 mg, 0.336mmol) was added to the reaction and stirred until dissolved then theamine reagent, (1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octanedihydrochloride (30 mg, 0.151 mmol), was added and the reaction cappedunder nitrogen and stirred at room temperature overnight. The reactionwas diluted with ethyl acetate and washed sequentially with 1.0N aqueoushydrochloric acid and brine. The organic phase was dried over MgSO4,filtered and solvent removed in vacuuo. The crude product was dried invacuuo at room temperature to yield 70 mg. The sample was purified on aShimadzu high pressure liquid chromatography system employing DiscoveryVP software interfaced with a SCL-10A controller, SIL-10A autosamplerand FRC-10A fraction collector. The sample was dissolved inacetonitrile/DMF (1:1) (2 mL) purified using a Waters Sunfire Prep C18OBD, 5 uM 19 mm×100 mm column and monitored using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 25 mL/min, a gradient of 70 solvent A/30%solvent B to 0% solvent A/100% solvent B, a gradient time of 15 minuteswith a run time of 20 minutes using % A=10% acetonitrile, 90% water,0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA.

Retention time of product was 5.56 minutes and remove volatiles/solventin vacuuo. HPLC analysis of the first Prep HPLC purification using %A=10 mM Ammonium Acetate, pH=6.8 in Water/Acetonitrile (95%/5%) % B=10mM Ammonium Acetate, pH=6.8 in Water/Acetonitrile (5%/95%) solventsystem show impurities in the sample. The sample was further purified ona Shimadzu high pressure liquid chromatography system employingDiscovery VP software interfaced with a SCL-10A controller, SIL-10Aautosampler and FRC-10A fraction collector. The sample was dissolved in0.5 ml DMF/1.5 ml acetonitrle and purified using a Phenonemex Gemini 30mm×100 mm column and monitored using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 40 mL/min, a gradient of 70 solvent A/30% solvent B to 0%solvent A/100% solvent B, a gradient time of 20 minutes with a run timeof 30 minutes using % A=10 mM Ammonium Acetate, pH=6.8 inWater/Acetonitrile (95%/5%) % B=10 mM Ammonium Acetate, pH=6.8 inWater/Acetonitrile (5%/95%) solvent system. Product elution time is from9.7 minutes to 11.7 minutes. Combine product fractions and removevolatiles and dry in vacuuo. The trifluoroacetic acid salt of the titlecompound was made by dissolving the purified product in dichloromethaneand adding 10 uL of trifluoroacetic acid then removing volatiles invacuuo. Drying in vacuuo at room temperature yielded 23.6 mg (35%) ofthe trifluoroacetic acid salt of the title compound as a yellowamorphous solid.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.11-1.29 (m, 1H) 1.32-1.45 (m, 3H)1.49 (dd, J=11.14, 6.87 Hz, 6H) 1.79 (d, J=10.68 Hz, 2H) 1.89-2.13 (m,4H) 2.28-2.73 (m, 15H) 2.84-2.95 (m, 1H) 3.25 (s, 2H) 3.39 (s, 2H)3.76-3.92 (m, 3H) 3.94 (s, 3H) 4.01-4.12 (m, 1H) 4.63 (d, J=15.87 Hz,1H) 4.87 (s, 1H) 6.96 (d, J=2.14 Hz, 2H) 7.13 (dd, J=8.85, 2.44 Hz, 1H)7.57 (d, J=8.55 Hz, 1H) 7.63 (s, 1H) 7.77 (s, 1H) 7.92 (d, J=8.55 Hz,1H) 10.06 (s, 1H).

LC-MS retention time 1.73 min; 723 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,6-[4-[[[2-[bis(1-methylethyl)amino]ethyl](1-methylethyl)amino]carbonyl]-1-methyl-1H-pyrazol-5-yl]-13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-

In a 2 dram vial, 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(52.1mg, 0.084 mmol) was dissolved in DMF (0.9 ml) and TBTU (56.2 mg, 0.175mmol) was added and the reaction stirred under a nitrogen atmosphere for1 hour at room temperature. DMAP (46 mg, 0.377 mmol) was added to thereaction and stirred until dissolved then the amine reagent,N,N,N′-triisopropylethylenediamine (55 mg, 0.295 mmol), was added andthe reaction capped under nitrogen and stirred at room temperatureovernight. The reaction was diluted with ethyl acetate and washedsequentially with 1.0N aqueous hydrochloric acid and brine. The organicphase was dried over MgSO4, filtered and solvent removed in vacuuo. Thecrude product was dried in vacuuo at room temperature to yield 84 mg asa yellow glass/film.

The sample was purified on a Shimadzu high pressure liquidchromatography system employing Discovery VP software interfaced with aSCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector.The sample was dissolved in acetonitrile/DMF (1:1) (2 mL) purified usinga Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column and monitoredusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 25 mL/min, a gradient of70 solvent A/30% solvent B to 0% solvent A/100% solvent B, a gradienttime of 15 minutes with a run time of 25 minutes using % A=10%acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1%TFA. The retention time of product=6 minutes. Combine product fractionsand remove volatiles in vacuuo using a rotary evaporator then dry samplein vacuuo at room temperature to yield 36.0 mg (47%) as a yellowamorphous solid.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.05 (s, 6H) 1.18-1.43 (m, 15H)1.46 (d, J=7.02 Hz, 8H) 1.78 (d, J=8.55 Hz, 2H) 1.87-2.12 (m, 4H) 2.62(s, 14H) 2.80-2.90 (m, 1H) 3.12 (s, 2H) 3.24-3.70 (m, 9H) 3.92 (s, 3H)3.97-4.06 (m, 1H) 4.19 (s, 1H) 4.55 (s, 1H) 4.99 (s, 1H) 6.86 (s, 1H)6.94 (d, J=2.44 Hz, 1H) 7.09 (dd, J=8.55, 2.75 Hz, 1H) 7.48-7.57 (m, 3H)7.85 (s, 1H) 7.90 (d, J=8.54 Hz, 1H) 9.33 (s, 1H) 10.12 (s, 1H).

LC-MS retention time 1.80 min; 783 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[[(2-methoxyphenyl)methyl](1-methylethyl)amino]carbonyl]-1-methyl-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-

In a 2 dram vial, 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(50mg, 0.081 mmol) was dissolved in DMF (811 μL) and TBTU (51.5 mg, 0.160mmol) was added and the reaction stirred under a nitrogen atmosphere for1.3 hour at room temperature. DMAP (52 mg, 0.426 mmol) was added to thereaction and stirred until dissolved then the amine reagent,N-(2-methoxybenzyl)propan-2-amine hydrochloride (36 mg, 0.167 mmol), wasadded and the reaction capped under nitrogen and stirred at roomtemperature overnight. The reaction was diluted with ethyl acetate andwashed sequentially with 1.0N aqueous hydrochloric acid and brine. Theorganic phase was dried over MgSO4, filtered and solvent removed invacuuo. The crude product was dried in vacuuo at room temperature toyield 75 mg as a yellow film.

The sample was purified on a Shimadzu high pressure liquidchromatography system employing Discovery VP software interfaced with aSCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector.The sample was dissolved in acetonitrile/DMF (1:1) (2 mL) purified usinga Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column and monitoredusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 25 mL/min, a gradient of70 solvent A/30% solvent B to 0% solvent A/100% solvent B, a gradienttime of 15 minutes with a run time of 25 minutes using % A=10%acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1%TFA Retention time of product=14.7 minutes. Remove volatiles fromproduct fraction in vacuuo using a rotary evaporator then dry sample invacuuo at room temperature to yield 45.4 mg (72%) as a amorphous yellowsolid. Proton NMR exhibits rotomeric characteristics.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.34-1.03 (m, 6.3H) 1.04-1.32 (m,3.4H) 1.29-1.66 (m, 7.6H) 1.78 (d, 2.2H) 1.90-2.24 (m, 4.3H) 2.52 (s,3.6H) 2.87 (s, 1.1H) 3.36-3.71 (m, 2.1H) 3.71-3.88 (m, 5.5H) 3.92 (s,3.4H) 4.00-4.06 (m, 0.8H) 4.13-4.39 (m, 1.1H) 4.63 (d, J=12.21 Hz, 1.0H)5.08 (d, J=14.04 Hz, 0.9H) 6.54-6.83 (m, 2.5H) 6.86-6.99 (m, 2.6H)7.02-7.20 (m, 2.1H) 7.34-7.71 (m, 3.1H) 7.74-7.99 (m, 2.0H) 9.39 (br.s,0.4H) 9.85 (br.s, 0.5H).

LC-MS retention time 1.99 min; 776 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 2 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[[(5-ethyl-1,3,4-oxadiazol-2-yl)methyl](1-methylethyl)amino]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

In a 2 dram vial, 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(50mg, 0.081 mmol) was dissolved in DMF (811 μL) and TBTU (51.5 mg, 0.160mmol) was added and the reaction stirred under a nitrogen atmosphere for1 hour at room temperature. DMAP (43.2 mg, 0.354 mmol) was added to thereaction and stirred until dissolved then the amine reagent,N-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)propan-2-amine (47.3 mg, 0.280mmol) dissolved in 0.2 ml of DMF, was added to the reaction. Thereaction was capped under nitrogen and stirred at room temperatureovernight.

The reaction was purified on a Shimadzu high pressure liquidchromatography system employing Discovery VP software interfaced with aSCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector.The reaction was diluted to 2 ml volume with acetonitrile and thereaction was purified using a Waters Sunfire Prep C18 OBD, 5 uM 19mm×100 mm column and monitored using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 25 mL/min, a gradient of 70 solvent A/30% solvent B to 0%solvent A/100% solvent B, a gradient time of 15 minutes with a run timeof 25 minutes using % A=10% acetonitrile, 90% water, 0.1% TFA % B=90%acetonitrile, 10% water, 0.1% TFA solvent system. Retention time ofproduct is 11.45 minutes. Combine product fractions and remove volatilesin vacuuo using a rotary evaporator then dry sample in vacuuo at roomtemperature to yield 47.8 mg as a yellow amorphous solid/film.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.07-1.24 (m, 5H) 1.27 (t, J=7.48Hz, 4H) 1.38 (d, J=5.49 Hz, 8H) 1.56 (d, J=9.46 Hz, 1H) 1.78 (d, J=9.46Hz, 2H) 1.88-1.99 (m, 1H) 2.00-2.17 (m, 3H) 2.55-2.82 (m, 4H) 2.83-2.94(m, 1H) 3.73 (s, 3H) 3.89 (s, 3H) 3.97-4.08 (m, 1H) 4.15-4.80 (m, 4H)5.22 (d, J=16.79 Hz, 1H) 6.88 (s, 1H) 6.94 (d, J=2.75 Hz, 1H) 7.04 (dd,J=8.55, 2.44 Hz, 1H) 7.46 (d, J=8.85 Hz, 1H) 7.59-7.67 (m, 2H) 7.91 (d,J=8.55 Hz, 1H) 8.31 (br.s, 1H) 9.62 (br.s, 1H).

LC-MS retention time 1.75 min; 766 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

1H-pyrazole-4-carboxylic acid,5-[10-[[(cyclobutylsulfonyl)amino]carbonyl]-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-,ethyl ester

Dissolve 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-(653mg, 1.210 mmol) in THF (12 ml) in a 50 ml RB flask. Carbonyldiimidazole(1.308 g, 8.07 mmol) was added to the reaction. The flask fitted with acondenser was placed under a nitrogen atmosphere and the reactionallowed to stir at room temperature for 1 hr then refluxed for 50minutes. The reaction was cooled under a nitrogen atmosphere andcyclobutanesulfonamide (825 mg, 6.10 mmol) was added to the reactionfollowed by DBU (0.383 ml, 2.54 mmol). The reaction was heated overnightat 70 C under a nitrogen atmosphere. LC-MS analysis indicated primarilyimidazolide but an insignificant amount of product, thereforecyclobutylsulfonamide (700 mg, 5.17 mmol) was added to the reactionfollowed by DBU (0.383 ml, 2.54 mmol). The reaction was heated to refluxunder a nitrogen atmosphere for 3.5 hours and progress rechecked byLCMS. Additional cyclobutylsulfonamide (357 mg, 2.64 mmol) and DBU(0.383 ml, 2.54 mmol) was added to the reaction and the reaction heatedto reflux for 3.25 hrs. The reaction was cooled and ethyl acetate andwashed two times with 1.0N aqueous hydrochloric acid. The aqueous layerwas back extracted with ethyl acetate. The organic layers were combinedand wash sequentially with 1.0N aqueous hydrochloric acid, 0.1M NaH2PO4,and again with 1.0N aqueous hydrochloric acid and finally brine. Theorganic phase was dried over magnesium sulfate, filtered and solventremoved in vacuuo to yield 949 mg of a crude product as a yellow solid.The crude product was adsorbed onto 2.6 g of silica gel andchromatographed on 28.7 g of silica gel slurry packed using 2% methanolin dichloromethane and eluted using 2% methanol in dichloromethane. Pureproduct fractions were combined and the volatiles removed in vacuuousing a rotary evaporator to yield 465 mg (59%) of the title compound asan amorphous yellow solid.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.20 (m, 1H) 1.30 (t, J=7.17 Hz,3H) 1.33-1.48 (m, 2H) 1.55 (br.s, 4H) 1.78 (d, J=9.46 Hz, 2H) 1.87-2.14(m, 6H) 2.32-2.42 (m, 2H) 2.55-2.69 (m, 2H) 2.79-2.92 (m, 1H) 3.28 (s, 3H) 3.90 (s, 3H) 4.25 (br.s, 2H) 4.53-4.63 (m, 1H) 4.71 (d, J=10.68 Hz,1H) 4.97 (d, J=14.34 Hz, 1H) 6.77 (s, 1H) 6.94 (d, J=2.44 Hz, 1H) 7.07(dd, J=8.55, 2.75 Hz, 1H) 7.35 (dd, J=8.39, 1.37 Hz, 1H) 7.52 (d, J=8.85Hz, 1H) 7.73 (d, J=1.22 Hz, 1H) 7.88 (d, J=8.55 Hz, 1H) 7.91 (s, 1H)8.24 (s, 1H).

LC-MS retention time 1.78 min; 655 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

1H-pyrazole-4-carboxylic acid,5-[10-[[(cyclobutylsulfonyl)amino]carbonyl]-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl-1-methyl-

1H-pyrazole-4-carboxylic acid,5-[10-[[(cyclobutylsulfonyl)amino]carbonyl]-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-,ethyl ester (463 mg, 0.705 mmol) was dissolved in THF (6.8 mL), thendiluted using methanol (6.8 mL) with heating and the mixture cooled toroom temperature. To the reaction suspension in THF/methanol was added1.0N aqueous sodium hydroxide (6.8 mL, 6.8 mmol). Upon addition of thesodium hydroxide solution the reaction became a clear homogeneoussolution. The reaction was stirred at room temperature under a nitrogenatmosphere for 20 hrs. Concentrate reaction in vacuuo using a rotaryevaporator with room temperature bath (20 C). Partition the reactionbetween 200 ml of ethyl acetate and 1.0N aqueous hydrochloric acid.Extract aqueous phase using ethyl acetate. Combine organic phases andwash sequentially with 1.0N aqueous hydrochloric acid and brine. Dry theorganic layer over magnesium sulfate, filter and remove volatiles fromthe filtrate in vacuuo to yield 457 mg of the title compound as a lightyellow colored solid.

1H NMR (500 MHz, MeOD) δ ppm 0.83 (br.s, 1H) 1.11-1.29 (m, 3H) 1.30-1.60(m, 4H) 1.74 (d, J=7.93 Hz, 2H) 1.87 (br.s, 1H) 1.94-2.07 (m, 5H)2.25-2.35 (m, 2H) 2.50-2.60 (m, 2H) 2.78-2.87 (m, 1H) 3.24 (s, 3H) 3.87(s, 3H) 4.46-4.55 (m, 1H) 4.67 (br.s, 1H) 4.99 (br.s, 1H) 6.78 (s, 1H)6.93 (d, J=2.44 Hz, 1H) 7.05 (dd, J=8.55, 2.75 Hz, 1H) 7.49 (d, J=8.55Hz, 1H) 7.52 (dd, J=8.55, 1.53 Hz, 1H) 7.81 (d, J=1.53 Hz, 1H) 7.84 (d,J=8.55 Hz, 1H) 7.89 (s, 1H).

LC-MS retention time 1.42 min; 627 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 4ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

General Procedure for Amide Couplings On

1H-pyrazole-4-carboxylic acid,5-[10-[[(cyclobutylsulfonyl)amino]carbonyl]-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-

Into a 2 dram vial place 639 ul of a stock solution containing1H-pyrazole-4-carboxylic acid,5-[10-[[(cyclobutylsulfonyl)amino]carbonyl]-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(0.639mL, 0.072 mmol) and TBTU (0.639 mL, 0.138 mmol) which was pre-mixed for1.25 hr at room temperature. To the reaction mixture add 239 ul of astock solution containing DMAP (0.239 mL, 0.358 mmol), then add theamine reagent (0.159 mmol). Cap the reaction under a nitrogen atmosphereand stir at room temperature overnight. The sample was purified on aShimadzu high pressure liquid chromatography system employing DiscoveryVP software interfaced with a SCL-10A controller, SIL-10A autosamplerand FRC-10A fraction collector. The sample was diluted to 2 ml (or 4 ml)using acetonitrile and purified using a Waters Sunfire Prep C18 OBD, 5uM 19 mm×100 mm column and monitored using a SPD-10AV UV-Vis detector ata detector wave length of 220 nM. The elution conditions employed a flowrate of 25 mL/min, a gradient of 70 solvent A/30% solvent B to 0%solvent A/100% solvent B, a gradient time of 15 minutes with a run timeof 20 minutes (or 25 minutes) using % A=10% acetonitrile, 90% water,0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA solvent system.Volatiles from the product fraction(s) are removed in vacuuo using aspeed vac overnight with heating.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.13-1.30 (m, 1H) 1.31-1.56 (m, 4H)1.79 (d, J=10.68 Hz, 2H) 1.88-2.15 (m, 7H) 2.37 (s, 4H) 2.54 (s, 4 H)2.67 (d, J=9.16 Hz, 4H) 2.83-2.96 (m, 2H) 3.05-3.64 (m, 5H) 3.89 (s, 3H)3.93 (s, 3H) 4.54-4.69 (m, 2H) 4.88 (s, 1H) 6.95 (t, J=2.14 Hz, 1H) 7.13(dd, J=8.70, 2.59 Hz, 1H) 7.57 (d, J=8.55 Hz, 1H) 7.60 (d, J=6.71 Hz,1H) 7.77 (s, 1H) 7.91 (d, J=8.24 Hz, 1H) 10.17 (s, 1H).

LC-MS retention time 1.55 min; 735 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-

See procedure for general amide coupling. The sample was purified on aShimadzu high pressure liquid chromatography system employing DiscoveryVP software interfaced with a SCL-10A controller, SIL-10A autosamplerand FRC-10A fraction collector. The sample was solubilized by dilutingto 2 ml using acetonitrile and purified using a Waters Sunfire Prep C18OBD, 5 uM 19 mm×100 mm column and monitored using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 25 mL/min, a gradient of 90% solvent A/10%solvent B to 0% solvent A/100% solvent B, a gradient time of 15 minuteswith a run time of 20 minutes using % A=10% acetonitrile, 90% water,0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA solvent system.Retention time of product=8.3 minutes.

1H NMR (500 MHz, CHLOROFORM-D) d ppm 0.99-1.32 (m, 7H) 1.32-1.66 (m, 3H)1.80 (d, J=8.55 Hz, 2H) 1.88-2.13 (m, 6H) 2.35 (s, 2H) 2.54 (s, 2H) 2.66(s, 2H) 2.92 (s, 2H) 3.02-3.71 (m, 10H) 3.80 (s, 3H) 3.93 (s, 3H) 4.08(s, 1H) 4.49-4.67 (m, 2H) 4.92 (d, J=12.21 Hz, 1H) 6.91 (s, 1H) 6.97 (d,J=2.44 Hz, 1H) 7.11 (dd, J=8.39, 2.29 Hz, 1H) 7.54 (d, J=8.54 Hz, 1H)7.56-7.65 (m, 2H) 7.78 (s, 1H) 7.92 (d, J=8.55 Hz, 1H) 9.71 (s, 1H).

LC-MS retention time 1.49 min; 737 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-3-methoxy-6-[1-methyl-4-(3-oxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1H-pyrazol-5-yl]-

See procedure for general amide coupling.

Sample was diluted to 4 ml using acetonitrile. The sample needed morethan 2 ml volume to completely solubilize in acetonitrile indicatinglower solubility than previous run samples.

The sample was purified on a Shimadzu high pressure liquidchromatography system employing Discovery VP software interfaced with aSCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector.The sample was diluted to 4 ml using acetonitrile and purified using aWaters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column and monitoredusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 25 mL/min, a gradient of70 solvent A/30% solvent B to 0% solvent A/100% solvent B, a gradienttime of 15 minutes with a run time of 20 minutes using % A=10%acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1%TFA solvent system. The purification was performed as two 2 mlinjections. Retention time of product was 13.9 minutes.

Volatiles from the product fractions were removed in vacuuo using aspeed vac overnight with heating. Weight of isolated title compound was38.6 mg.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.85 (m, 1H) 1.21 (m, 2H) 1.31-1.57(m, 6H) 1.77 (d, J=8.24 Hz, 3H) 1.89-2.14 (m, 6H) 2.15-2.24 (m, 1H) 2.30(d, J=11.29 Hz, 1H) 2.34-2.43 (m, 2H) 2.57-2.79 (m, 2H) 2.86 (t, J=10.53Hz, 1H) 2.94-3.41 (m, 9H) 3.51 (d, J=14.65 Hz, 1H) 3.62 (d, J=10.68 Hz,1H) 3.86 (s, 1H) 3.93 (s, 5H) 4.51-4.68 (m, 2H) 4.83-5.06 (m, 1H)6.78-6.89 (m, 1H) 6.94 (d, J=2.44 Hz, 1H) 7.08-7.17 (m, 1H) 7.58 (d,J=8.54 Hz, 1H) 7.63 (d, J=7.93 Hz, 1H) 7.66-7.81 (m, 2H) 7.90 (t, J=9.16Hz, 1H) 10.19 (s, 0.2H) 10.44 (s, 0.7H).

LC-MS retention time 1.62 min; 736 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-

See procedure for general amide coupling.

The sample was purified on a Shimadzu high pressure liquidchromatography system employing Discovery VP software interfaced with aSCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector.The sample was diluted to 2 ml using acetonitrile and purified using aWaters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column and monitoredusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 25 mL/min, a gradient of70 solvent A/30% solvent B to 0% solvent A/100% solvent B, a gradienttime of 15 minutes with a run time of 25 minutes using % A=10%acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1%TFA solvent system. Retention time of product=13.5 minutes.

Volatiles from the product fractions were removed in vacuuo using aspeed vac overnight with heating.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.68 (br.s, 3H) 0.78 (m, 1H)0.81-0.91 (m, 1H) 1.12-1.32 (m, 2H) 1.32-1.50 (m, 3H) 1.79 (d, J=11.29Hz, 2H) 1.90-2.01 (m, 3H) 2.01-2.16 (m, 5H) 2.18-2.27 (m, 1H) 2.28-2.36(m, 1H) 2.35-2.46 (m, 1H) 2.60-2.82 (m, 3H) 2.83-3.11 (m, 5H) 3.12-3.31(m, 2H) 3.42 (s, 1H) 3.81-3.94 (m, 3H) 3.94 (s, 3H) 4.51-4.70 (m, 2H)4.90 (d, J=14.34 Hz, 1H) 6.79-6.90 (m, 1H) 6.95 (d, J=1.83 Hz, 1H) 7.13(dd, J=8.55, 2.14 Hz, 1H) 7.60 (dd, J=24.57, 8.39 Hz, 2H) 7.69 (d,J=16.48 Hz, 1H) 7.91 (d, J=8.24 Hz, 1H) 10.03 (s, 0.3H) 10.42 (s, 0.7H).

LC-MS retention time 1.85 min; 724 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 4ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 2 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-

Into a 2 dram vial place 639 ul of a stock solution containing1H-pyrazole-4-carboxylic acid,5-[10-[[(cyclobutylsulfonyl)amino]carbonyl]-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(0.639mL, 0.072 mmol) and TBTU (0.639 mL, 0.138 mmol) which was pre-mixed for1.25 hr at room temperature. To the reaction mixture add 239 ul of astock solution containing DMAP (0.239 mL, 0.358 mmol), then add theamine reagent 3,7-dioxa-9-azabicyclo[3.3.1]nonane hydrochloride (38.0mg, 0.229 mmol). Cap the reaction under a nitrogen atmosphere and stirat room temperature. Analysis of the reaction mixture by LCMS indicatedonly a trace of product present. The reaction was allowed to sit cappedat room temperature for 3 days then HATU (92 mg, 0.242 mmol). Thereaction was capped and stirred at room temperature overnight. LCMSindicated a complete reaction. The reaction was allowed to stir at roomtemperature for 2 more days (weekend).

The sample was purified on a Shimadzu high pressure liquidchromatography system employing Discovery VP software interfaced with aSCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector.The reaction was diluted to 2 ml using acetonitrile and purified using aWaters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column and monitoredusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 25 mL/min, a gradient of70 solvent A/30% solvent B to 0% solvent A/100% solvent B, a gradienttime of 15 minutes with a run time of 25 minutes using % A=10%acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1%TFA solvent system. The retention time of product was observed as splitpeaks at 10.72 min and 11.03 minutes. Volatiles from the productfractions were removed in vacuuo using a speed vac overnight withheating.

1H NMR analysis of each product fraction provided identical NMRspectrums. The product fraction were combined and into a vial and driedin vacuuo at room temperature to yield 34.5 mg (65%) of the titlecompound as a yellow amorphous solid.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.11-1.27 (m, 1H) 1.31-1.52 (m, 3H)1.71-1.83 (m, J=8.85 Hz, 2H) 1.92-2.15 (m, 6H) 2.31 (s, 1H) 2.38 (s, 1H)2.55-2.77 (m, 3H) 2.81-2.91 (m, 1H) 3.25 (s, 1H) 3.33 (d, J=9.46 Hz, 1H)3.42 (s, 2H) 3.55 (d, J=10.07 Hz, 1H) 3.62-3.80 (m, 3H) 3.89 (s, 3H)3.93 (s, 3H) 4.23 (s, 3H) 4.53-4.66 (m, 2H) 4.93 (d, J=15.26 Hz, 1H)6.87 (s, 1H) 6.95 (d, J=2.44 Hz, 1H) 7.13 (dd, J=8.54, 2.75 Hz, 1H) 7.58(d, J=8.55 Hz, 1H) 7.61 (d, J=8.55 Hz, 1H) 7.70 (s, 1H) 7.74 (s, 1H)7.93 (d, J=8.54 Hz, 1H) 10.09 (s, 1H).

LC-MS retention time 1.50 min; 738 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-

Into a 2 dram vial place 787 ul of a stock solution containing1H-pyrazole-4-carboxylic acid,5-[10-[[(cyclobutylsulfonyl)amino]carbonyl]-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(0.091M)(0.787 mL, 0.072 mmol) and TBTU (0.213M) (0.787 mL, 0.168 mmol) whichwas pre-mixed for 1.25 hr at room temperature. To the reaction mixtureadd DMAP (48.0 mg, 0.393 mmol), then add the amine reagent then add theamine reagent, in this case, (S)-2-(methoxymethyl)morpholinehydrochloride (30.4 mg, 0.181 mmol). Cap the reaction under a nitrogenatmosphere and stir at room temperature overnight. The reaction isdiluted with acetonitrile and purified by reverse phase Prep HPLC.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.19 (m, 1H) 1.31-1.54 (m, 3H) 1.79(d, J=10.38 Hz, 2H) 1.90-2.20 (m, 7H) 2.23-2.55 (m, 3H) 2.58-2.82 (m,4H) 2.82-3.13 (m, 6H) 3.11-3.49 (m, 5H) 3.90 (s, 3H) 3.94 (s, 3H)4.51-4.67 (m, 2H) 4.78-4.96 (m, 1H) 6.85 (s, 1H) 6.95 (s, 1H) 7.12 (dd,J=8.55, 2.44 Hz, 1H) 7.56 (d, J=8.55 Hz, 1H) 7.59 (d, J=7.63 Hz, 1H)7.63-7.74 (m, 2H) 7.90 (t, J=9.00 Hz, 1H) 10.09 (s, 0.3H) 10.41 (s,0.6H).

LC-MS retention time 1.62 min; 740 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 2 min, and ananalysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

The following examples can be prepared in an analogous fashion.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-6-[4-[[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-

HPLC Method: The sample was purified on a Shimadzu high pressure liquidchromatography system employing Discovery VP software interfaced with aSCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector.The reaction mixture was diluted to 2 ml using acetonitrile and purifiedusing a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column andmonitored using a SPD-10AV UV-Vis detector at a detector wave length of220 nM. The elution conditions employed a flow rate of 25 mL/min, agradient of 70 solvent A/30% solvent B to 0% solvent A/100% solvent B, agradient time of 15 minutes with a run time of 20 minutes using % A=10%acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1%TFA solvent system. The product retention time is 5.71 minutes.Volatiles from the product fractions were removed in vacuuo using aspeed vac with a medium heat setting.

The proton NMR of this sample exhibited characteristics of rotomers.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.49 (s, 0.3H) 0.96-1.29 (m, 2.2H)1.30-1.59 (m, 3.3H) 1.79 (d, J=11.60 Hz, 1.8H) 1.86-2.17 (m, 3.8H)2.19-2.46 (m, 2.1H) 2.49-3.74 (m, 6.4H) 3.76-4.21 (m, 5.1H) 4.24-4.39(m, 0.8H) 4.43-4.70 (m, 1.4H) 4.73-5.07 (m, 1.0H) 5.23 (s, 0.1H) 6.73(d, J=29.30 Hz, 0.4H) 6.88-7.00 (m, 0.8H) 7.04-7.13 (m, 0.7H) 7.44-7.60(m, 0.9H) 7.58-7.96 (m, 2.0H) 8.19 (s, 0.1H) 10.43 (d, J=81.79 Hz, 0.4H)11.20 (d, J=87.28 Hz, 0.5H) 12.46 (s, 0.6H)

LC-MS retention time 1.60 min; 737 m/z (MH⁺). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-6-[4-[[3-(dimethylamino)-1-piperidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-

HPLC Method: The sample was purified on a Shimadzu high pressure liquidchromatography system employing Discovery VP software interfaced with aSCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector.The reaction was diluted to 4 ml using acetonitrile with a very smallamount of methanol and purified using a Waters Sunfire Prep C18 OBD, 5uM 19 mm×100 mm column and monitored using a SPD-10AV UV-Vis detector ata detector wave length of 220 nM. The elution conditions employed a flowrate of 25 mL/min, a gradient of 70 solvent A/30% solvent B to 0%solvent A/100% solvent B, a gradient time of 15 minutes with a run timeof 20 minutes using % A=10% acetonitrile, 90% water, 0.1% TFA % B=90%acetonitrile, 10% water, 0.1% TFA solvent system. The retention time ofproduct was 5.37 minutes. The compound was purified as two 2 mlinjections.

Peaks in proton NMR spectra are generally broad, characteristic ofrestricted rotation in molecule.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.13-1.32 (m, 2H) 1.32-1.59 (m, 5H)1.79 (s, 3H) 1.89-2.18 (m, 7H) 2.36 (s, 2H) 2.48-2.76 (m, 8H) 2.88 (s,1H) 3.51 (s, 1H) 3.60-3.91 (m, 7H) 3.93 (s, 3H) 4.24 (s, 0.6H) 4.47-4.68(m, 2H) 4.84 (d, J=13.43 Hz, 1H) 6.86-6.98 (m, 1H) 7.07-7.17 (m, 1H)7.53 (d, J=8.55 Hz, 1H) 7.58-7.84 (m, 2H) 7.93 (d, J=7.93 Hz, 1H) 10.07(s, 1H).

LC-MS retention time 1.56 min; 739 m/z (MH+). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-

HPLC Method: The sample was purified on a Shimadzu high pressure liquidchromatography system employing Discovery VP software interfaced with aSCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector.The reaction mixture was diluted to 4 ml using acetonitrile and purifiedusing a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column andmonitored using a SPD-10AV UV-Vis detector at a detector wave length of220 nM. The elution conditions employed a flow rate of 25 mL/min, agradient of 50% solvent A/50% solvent B to 0% solvent A/100% solvent B,a gradient time of 15 minutes with a run time of 20 minutes using %A=10% acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water,0.1% TFA solvent system. The compound was purified as two 2 mlinjections.

Volatiles from the product fractions were removed in vacuuo using aspeed vac overnight with heating. The product fractions were combinedusing dichloromethane and solvent removed in vacuuo to give 35.4 mg(71%) of the title compound as a yellow amorphous solid.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.22 (m, 1H) 1.33-1.55 (m, 3H) 1.79(d, J=10.68 Hz, 2H) 1.91-2.21 (m, 7H) 2.37 (d, J=29.60 Hz, 3H) 2.56-2.79(m, 4H) 2.78-2.96 (m, 4H) 3.12 (s, 3H) 3.90 (s, 3H) 3.94 (s, 3H)4.53-4.65 (m, 2H) 4.89 (d, J=14.95 Hz, 1H) 6.86 (s, 1H) 6.95 (d, J=2.44Hz, 1H) 7.12 (dd, J=8.70, 2.59 Hz, 1H) 7.57 (d, J=8.85 Hz, 1H) 7.59 (d,J=8.55 Hz, 1H) 7.67 (s, 1H) 7.69 (s, 1H) 7.93 (d, J=8.54 Hz, 1H) 10.24(s, 1H).

LCMS for 74814-024-a: LC-MS retention time 1.61 min; 696 m/z (MH−). LCdata was recorded on a Shimadzu LC-10AS liquid chromatograph equippedwith a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 5 ml/min, a gradient of 100% solvent A/0%solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, ahold time of 1 min, and an analysis time of 4 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS data was determined using aMicromass Platform for LC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-6-[4-[(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-

HPLC Method: The sample was purified on a Shimadzu high pressure liquidchromatography system employing Discovery VP software interfaced with aSCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector.The reaction was diluted to 4 ml using acetonitrile and a trace ofmethanol and in purified using a Waters Sunfire Prep C18 OBD, 5 uM 19mm×100 mm column and monitored using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 25 mL/min, a gradient of 70 solvent A/30% solvent B to 0%solvent A/100% solvent B, a gradient time of 15 minutes with a run timeof 25 minutes using % A=10% acetonitrile, 90% water, 0.1% TFA % B=90%acetonitrile, 10% water, 0.1% TFA solvent system. Retention time ofproduct=5.72 minutes.

The compound was purified as two 2 ml injections. Volatiles were removedfrom the product fractions in vacuuo overnight using a speed-vac set atmedium heating.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.24 (s, 1H) 1.30-1.45 (m, 2H)1.31-1.45 (m, 2H) 1.58 (none, 2H) 1.78 (s, 4H) 1.88-2.24 (m, 9H) 2.34(s, 2H) 2.65 (s, 3H) 2.74-3.18 (m, 3H) 3.18-3.87 (m, 9H) 3.89-3.96 (m,3H) 3.96-4.35 (m, 3H) 4.45-4.68 (m, 2H) 4.76-5.00 (m, 1H) 6.80-6.95 (m,1H) 6.96 (s, 1H) 7.05-7.15 (m, J=8.24 Hz, 1H) 7.47-7.68 (m, 3H)7.68-7.81 (m, 1H) 7.88 (s, 1H) 9.94 (s, 1H) 12.54 (s, 1H).

LC-MS retention time 1.61 min; 735 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[[(1-methylethyl)[(tetrahydro-2-furanyl)methyl]amino]carbonyl]-1H-pyrazol-5-yl]-

In a 2 dram vial, 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(51.1mg, 0.083 mmol) was dissolved in DMF (829 μl) and HATU (66.3 mg, 0.174mmol) was added to the reaction. The reaction was stirred under anitrogen atmosphere for 1.2 hours at room temperature. DMAP (41.5 mg,0.340 mmol) was added to the reaction and stirred until dissolved thenthe amine reagent, Isopropyl-(tetrahydro-furan-2-ylmethyl)-amine (36 μl,0.251 mmol), was added and the reaction capped under nitrogen andstirred at room temperature for 17 hours. Note-assume density of aminereagent is 1 g/cc, important aspect is not exact stoichiometry butexcess amine present. The product was purified on a Shimadzu highpressure liquid chromatography system employing Discovery VP softwareinterfaced with a SCL-10A controller, SIL-10A autosampler and FRC-10Afraction collector. The sample was dissolved in acetonitrile/DMF (1:1)(2 ml) and purified using a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100mm column and monitored using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 25mL/min, a gradient of 70 solvent A/30% solvent B to 0% solvent A/100%solvent B, a gradient time of 15 minutes with a run time of 25 minutesusing % A=10% acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile,10% water, 0.1% TFA solvent system. Retention time of product is 13.3minutes. Take product fraction and remove volatiles in vacuuo using arotary evaporator. The title compound was isolated (47.4 mg, 77%) as anamorphous yellow solid. Proton NMR spectra exhibits characteristics ofrestricted rotation (broad and rotomeric peaks).

1H NMR (500 MHz, CHLOROFORM-D) d ppm 0.61 (s, 1.6H) 0.80-1.11 (m, 5.1H)1.23 (s, 2.7H) 1.31-1.57 (m, 10.7H) 1.76 (s, 4.0H) 1.87-2.13 (m, 5.9H)2.20 (s, 2.4H) 2.38-2.75 (m, 0.7H) 2.78-2.92 (m, 1.2H) 3.06-3.25 (m,1.3H) 3.37-3.82 (m, 6.9H) 3.91 (s, 3.9H) 3.97-4.27 (m, 2.0H) 4.56 (d,J=12.82 Hz, 0.9H) 4.93-5.23 (m, 0.9H) 6.87 (s, 1.0H) 6.94 (d, J=2.44 Hz,1.0H) 7.07 (d, J=7.93 Hz, 1.0H) 7.51 (d, J=7.93 Hz, 1.1H) 7.57 (s, 2.2H)7.81-8.01 (m, 2.1H) 9.48-9.81 (m, 0.6H) 9.98 (s, 0.5H).

LC-MS retention time 1.76 min; 740 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylcarbonyl)-1H-pyrazol-5-yl]-

In a 2 dram vial, 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-(50.8mg, 0.082 mmol) was dissolved in DMF (824 μL) and HATU (72.2 mg, 0.190mmol) was added and the reaction stirred under a nitrogen atmosphere for1 hour at room temperature. DMAP (41.8 mg, 0.342 mmol) was added to thereaction and stirred until dissolved then the amine reagent,8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (30.6 mg, 0.205 mmol). Thereaction capped under nitrogen and stirred at room temperatureovernight. The product was purified on a Shimadzu high pressure liquidchromatography system employing Discovery VP software interfaced with aSCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector.The reaction was acidified with aqueous acetic acid then diluted to 2 mlwith acetonitrile and filtered using a 0.45 uM syringe filter. Thefiltrate was purified using a Waters Sunfire Prep C18 OBD, 5 uM 19mm×100 mm column and monitored using a SPD-10AV UV-Vis detector at adetector wave length of 220 nM. The elution conditions employed a flowrate of 25 mL/min, a gradient of 70 solvent A/30% solvent B to 0%solvent A/100% solvent B, a gradient time of 20 minutes with a run timeof 25 minutes using % A=10% acetonitrile, 90% water, 0.1% TFA % B=90%acetonitrile, 10% water, 0.1% TFA solvent system. The product wascollected as a single fraction from 13.99 to 14.70 minutes. Volatilesfrom the product fraction were removed in vacuuo using a speed vac atmedium heat setting.

The title compound was isolated (46.0 mg, 78% yield) as a yellowamorphous solid.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.26-1.05 (m, 1.2H) 1.14-1.32 (m,1.9H) 1.33-1.45 (m, 2.3H) 1.49 (dd, J=14.04, 6.71 Hz, 7.1H) 1.53-1.72(m, 3.4H) 1.79 (d, J=9.77 Hz, 2.2H) 1.97 (d, J=10.99 Hz, 1.2H) 2.02-2.15(m, 3.1H) 2.27 (d, J=11.29 Hz, 0.7H) 2.86 (t, J=11.60 Hz, 1.6H) 3.02 (d,J=8.85 Hz, 1.5H) 3.16 (s, 3.9H) 3.32 (d, J=11.60 Hz, 1.1H) 3.73-3.87 (m,2.1H) 3.90 (s, 2.8H) 3.92-3.97 (m, 3.4H) 4.00-4.11 (m, 1.4H) 4.59 (d,J=15.26 Hz, 1.0H) 4.86 (d, J=14.34 Hz, 0.8H) 5.04 (s, 0.3H) 6.86 (s,1.0H) 6.95 (s, 1.0H) 7.11 (dd, J=8.55, 2.44 Hz, 1.0H) 7.54 (d, J=8.85Hz, 1.2H) 7.57-7.77 (m, 2.7H) 7.80-8.02 (m, 1.3H) 9.74 (s, 0.2H) 10.11(s, 0.7H).

LC-MS retention time 1.61 min; 710 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

13-cyclohexyl-6-((2E,Z)-3-(dimethylamino)-2-(ethoxycarbonyl)-2-propenoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid

In a 50 ml round bottom flask dissolve tert-butyl13-cyclohexyl-6-((2E,Z)-3-(dimethylamino)-2-(ethoxycarbonyl)-2-propenoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(538 mg, 0.879 mmol) in 1,2-dichloroethane (5 mL) then add TFA (5 mL).The reaction mixture turned a darker reddish color upon addition of TFA.Place the reaction under a nitrogen atmosphere and stir at roomtemperature for 2.25 hrs. Remove volatiles in vacuuo using a rotaryevaporator, dissolve oily red residue in dichloromethane/benzene andremove volatiles in vacuuo on rotary evaporator. Take resulting red oildissolve in ethyl acetate wash with 1.0N aqueous hydrochloric acid. Theaqueous layer was back extracted with ethyl acetate. The organic layerswere combined and sequentially washed with 1.0N aqueous hydrochloricacid and brine. The organic layer was dried over MgSO4, filtered and thesolvents removed in vacuuo to give a reddish-orange oil which wasdissolved in benzene and volatiles removed in vacuuo to yield 519 mg ofthe title compound a red-orange foam. The compound was used withoutfurther purification.

LC-MS retention time 1.86 min; 555 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[1-(1,1-dimethylethyl)-4-(ethoxycarbonyl)-1H-pyrazol-5-yl]-3-methoxy-

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[(2E,Z)-3-(dimethylamino)-2-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-oxo-2-propenyl]-3-methoxy-(101mg, 0.181 mmol) was dissolved in ethanol (726 μL) and dioxane (181 μL).Triethyl amine (59 μL, 0.423 mmol) was added to the reaction followed bythe hydrazine reagent, tert-butylhydrazine hydrochloride (23.6 mg, 0.189mmol). The reaction was capped under a nitrogen atmosphere and heated ina microwave to 160 C for 45 minutes. The reaction was concentrated invacuuo using a rotary evaporator and the residue was dissolved in ethylacetate and washed sequentially with 1.0N aqueous hydrochloric acid thenbrine. The organic layer was dried over magnesium sulfate, filtered andvolatiles removed in vacuuo to give 91 mg of a yellow amorphous solid.The product was purified on a Shimadzu high pressure liquidchromatography system employing Discovery VP software interfaced with aSCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector.The sample was dissolved in acetonitrile/DMF mixture purified using aWaters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column and monitoredusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 25 mL/min, a gradient of70 solvent A/30% solvent B to 0% solvent A/100% solvent B, a gradienttime of 20 minutes with a run time of 30 minutes using % A=10%acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1%TFA solvent system.

The above isomeric major product retention time was 18.54 minutes. Theminor region-isomeric alkylated pyrazole was collected with retentiontime of 20.54 minutes.

The volatiles were removed from product fractions in vacuuo to obtain29.8 mg of the title compound as a yellow amorphous solid.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.09 (s, 9H) 1.18-1.56 (m, 8H) 1.63(d, 1H) 1.78 (d, J=8.55 Hz, 2H) 1.88-2.22 (m, 5H) 2.89 (t, J=11.75 Hz,1H) 3.89 (s, 3H) 4.27 (s, 2H) 4.84 (d, J=14.65 Hz, 1H) 4.96 (d, J=14.95Hz, 1H) 6.81 (s, 1H) 6.90 (d, J=2.14 Hz, 1H) 7.05 (dd, J=8.70, 2.59 Hz,1H) 7.52 (d, J=8.54 Hz, 1H) 7.76 (dd, J=8.55, 1.22 Hz, 1H) 7.88 (d,J=8.55 Hz, 1H) 7.92 (s, 1H) 8.01 (s, 1H).

LC-MS retention time 2.20 min; 580 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(1,1-dimethylethyl)-,ethyl ester

In a 2 dram vial, 7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[1-(1,1-dimethylethyl)-4-(ethoxycarbonyl)-1H-pyrazol-5-yl]-3-methoxy-(139mg, 0.239 mmol) was dissolved in dichloromethane (2.4 ml) andpropane-2-sulfonamide (98 mg, 0.796 mmol) and DMAP (90 mg, 0.737 mmol)were added to the reaction followed by EDC (70.3 mg, 0.367 mmol). Thereaction was capped under a nitrogen atmosphere and stirred at roomtemperature for 18 hrs. The reaction was monitored by HPLC then allowedto continue stirring under a nitrogen atmosphere at room temperature for24 hrs.

Subsequent HPLC analysis revealed no discernable change in reactioncomposition over the last 24 hrs. Volatiles were removed from thereaction in vacuuo using a rotary evaporator and the reaction residuewas diluted with ethyl acetate and washed sequentially with 1.0N aqueoushydrochloric acid, 0.1M aqueous NaH2PO4 and 1.0N aqueous hydrochloricacid then brine. The organic phase was dried over MgSO4, filtered andsolvent removed in vacuuo. The product was dried in vacuuo at roomtemperature to give 165 mg of product as an amorphous yellow solid. Theproduct was used without any further purification.

LC-MS retention time 2.03 min; 685 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(1,1-dimethylethyl)-

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(1,1-dimethylethyl)-,ethyl ester (164 mg, 0.239 mmol) was dissolved in THF (3 mL) andmethanol (3.00 mL) then 1.0 N aqueous sodium hydroxide (3.00 mL) wasadded to the reaction and the reaction was placed under a nitrogenatmosphere and stirred at room temperature for 25 hrs. The reaction wasconcentrated in vacuuo using a rotary evaporator without heating thenpartitioned between ethyl acetate and 1.0N aqueous hydrochloric acid.Wash ethyl acetate with 1N aqueous hydrochloric acid, combine aqueouslayers and back extract with ethyl acetate. The organic layers werecombined and wash with brine, dry over magnesium sulfate and solventremoved in vacuuo using a rotary evaporator. The product was dried invacuuo at room temperature to give 158.4 mg as a yellow amorphous solid.The product was carried on without any further purification.

LC-MS retention time 1.54 min; 657 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-(1,1-dimethylethyl)-4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(1,1-dimethylethyl)-(60mg, 0.091 mmol) was dissolved in DMF (911 μL). HATU (81.5 mg, 0.214mmol) was added to the reaction and the reaction was capped under anitrogen atmosphere and stir at room temperature for 1.25 hrs. DMAP(45.9 mg, 0.376 mmol) was added to reaction followed by amine reagent,(2R,6S)-2,6-dimethylmorpholine (34 μL, 0.275 mmol). The reaction wascapped under a nitrogen atmosphere and stir at room temperature for 18hr. The product was purified on a Shimadzu high pressure liquidchromatography system employing Discovery VP software interfaced with aSCL-10A controller, SIL-10A autosampler and FRC-10A fraction collector.The reaction was diluted to 2 ml with acetonitrile and a couple of dropsof aqueous acetic acid then purified using a Waters Sunfire Prep C18OBD, 5 uM 19 mm×100 mm column and monitored using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 25 mL/min, a gradient of 70 solvent A/30%solvent B to 0% solvent A/100% solvent B, a gradient time of 20 minuteswith a run time of 30 minutes using % A=10% acetonitrile, 90% water,0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA solvent system.Retention time of product was 18.5 minutes. Product fractions werecombined and volatiles removed in vacuuo using a rotary evaporator. Thesample was dried in vacuuo at room temperature to give 32.5 mg as ayellow amorphous film. 1H NMR results are characteristic of restrictedrotation with broadening and splitting of peaks.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.66 (d, J=6.10 Hz, 2.4H) 0.71 (d,J=6.10 Hz, 2.3H) 0.78 (dd, J=11.29, 6.10 Hz, 1.8H) 1.10 (s, 1.2H) 1.25(dd, J=13.73, 6.71 Hz, 3.0H) 1.35-1.44 (m, 2.5H) 1.46 (t, J=7.02 Hz,4.7H) 1.54 (d, J=6.71 Hz, 3.7H) 1.67 (s, 0.6H) 1.71 (s, 6.8H) 1.72-1.75(m, 2.7H) 1.79 (d, J=11.90 Hz, 2.5H) 1.83-1.92 (m, 1.0H) 1.98 (d,J=12.51 Hz, 2.2H) 2.02-2.21 (m, 7.9H) 2.21-2.30 (m, 1.4H) 2.80-2.95 (m,2.3H) 3.04 (d, J=42.42 Hz, 0.6H) 3.23 (d, J=13.73 Hz, 0.3H) 3.34 (d,J=12.82 Hz, 0.8H) 3.92 (d, J=4.88 Hz, 0.5H) 3.95 (s, 3.0H) 4.04-4.13 (m,1.1H) 4.49-4.58 (m, 1.0H) 4.79 (d, J=14.65 Hz, 0.3H) 4.86 (d, J=15.26Hz, 0.7H) 6.78 (s, 0.8H) 6.85 (s, 0.3H) 6.87 (d, J=2.75 Hz, 0.8H) 6.91(s, 0.3H) 7.14 (dd, J=8.55, 2.44 Hz, 1.0H) 7.55-7.60 (m, 0.9H) 7.60-7.64(m, 2.3H) 7.64-7.68 (m, 1.0H) 7.83-7.95 (m, 1.3H) 10.32 (s, 0.3H) 10.60(s, 0.7H).

LC-MS retention time 2.10 min; 754 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-(1,1-dimethylethyl)-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(1,1-dimethylethyl)-(48.8mg, 0.074 mmol) was dissolved in DMF (741 μL). HATU (65.3 mg, 0.172mmol) was added to the reaction and the reaction was capped under anitrogen atmosphere and stir at room temperature for 1 hrs. DMAP (53.8mg, 0.440 mmol) was added to reaction followed by amine reagent,(2R,6S)-1,2,6-trimethylpiperazine dihydrochloride (34.5 mg, 0.172 mmol).The reaction was capped under a nitrogen atmosphere and stir at roomtemperature for 18 hr. The product was purified on a Shimadzu highpressure liquid chromatography system employing Discovery VP softwareinterfaced with a SCL-10A controller, SIL-10A autosampler and FRC-10Afraction collector. The reaction was acidified with a few drops ofaqueous acetic acid and diluted to 2 ml with acetonitrile then purifiedusing a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×100 mm column andmonitored using a SPD-10AV UV-Vis detector at a detector wave length of220 nM. The elution conditions employed a flow rate of 25 mL/min, agradient of 70 solvent A/30% solvent B to 0% solvent A/100% solvent B, agradient time of 20 minutes with a run time of 25 minutes using % A=10%acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water, 0.1%TFA solvent system. Product was collected from 8.14 minutes to 9.45minutes. Volatiles were removed in vacuuo from the combined productfractions to ultimately yield 11.1 mg of the title compound as a yellowamorphous film.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.93-1.34 (m, 9.7H) 1.37-1.52 (m,9.5H) 1.56-1.68 (m, 1.6H) 1.68-1.83 (m, 9.2H) 1.87-2.20 (m, 5.4H)2.28-2.52 (m, 2.0H) 2.55-3.01 (m, 9.4H) 3.19 (d, J=40.59 Hz, 0.8H) 3.63(d, J=134.28 Hz, 2.4H) 3.83-4.04 (m, 4.0H) 4.54 (d, J=14.65 Hz, 0.8H)4.76 (d, J=14.34 Hz, 0.8H) 6.72-6.97 (m, 2.0H) 7.08 (d, J=7.32 Hz, 1.0H)7.36-7.76 (m, 3.4H) 7.88 (s, 1.2H) 10.86 (s, 0.5H) 11.26 (s, 0.4H).

LC-MS retention time 1.81 min; 767 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[3-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-1,3-dioxopropyl]-3-methoxy-,1,1-dimethylethyl ester

In a 250 ml round bottom flask dissolve tert-butyl13-cyclohexyl-6-(3-ethoxy-3-oxopropanoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-10-carboxylate(3.13 g, 5.61 mmol) in toluene (56 mL) and addcis-2,6-Dimethylmorpholine (2.6 mL, 20.99 mmol) to the reaction. Placereaction under a nitrogen atmosphere and heat to reflux for 9 hours. Thereaction was partitioned between ethyl acetate and 1.0M aqueous citricacid. The organic layer was washed sequentially with 1.0M aqueous citricacid, 0.1M NaH2PO4, and brine. Dry organic phase over magnesium sulfate,filter and remove solvent in vacuuo to give 3.01 g of crude product as aorange-amber foam. Dissolve the crude product in dichloromethane andadsorb onto 8.2 g of silica gel. Chromatograph crude product on 90 g ofsilica gel slurry packed in 5% ethyl acetate in dichloromethane, elutewith gradient of 5% ethyl acetate in dichloromethane to 10% ethylacetate in dichloromethane. Pure product fractions were combined andsolvent removed in vacuuo using a rotary evaporator to yield a yellowamorphous solid which was further dried in vacuuo at room temperature toyield 1.28 g of the title compound. Less pure fractions yielded another0.48 g of product. LCMS analysis gave two peaks of equivalent mass tothat of the desired product. Resolution of the two peaks by Prep HPLCunder the following conditions yielded peaks which inter-converted whenanalyzed after isolation: Shimadzu high pressure liquid chromatographysystem employing Discovery VP software interfaced with a SCL-10Acontroller, SIL-10A autosampler and FRC-10A fraction collector. Thesample 76816-035-a (63 mg) was dissolved in acetonitrile/DMF mixture(2:1, 2 ml) purified using a Phenonmenex Luna C18 30×100 mm 10u columnand monitored using a SPD-10AV UV-Vis detector at a detector wave lengthof 220 nM. The elution conditions employed a flow rate of 40 mL/min, agradient of 60% solvent A/40% solvent B to 0% solvent A/100% solvent B,a gradient time of 15 minutes with a run time of 25 minutes using % A=10mM Ammonium Acetate in 95:5 Water/Acetonitrile % B=10 mM AmmoniumAcetate in 5:95 Water/Acetonitrile solvent system. Two peaks wereisolated from the sample: First peak at RT=16.3 minutes. Both samplesexhibited identical HPLC spectra after isolation indicatinginter-conversion.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.89 (s, 2.0H) 1.01 (s, 3.3H) 1.19(d, J=26.25 Hz, 3.5H) 1.30-1.47 (m, 4.5H) 1.55 (s, 4.2H) 1.60 (s, 3.6H)1.63 (s, 9.0H) 1.76 (d, J=8.24 Hz, 3.1H) 1.93 (d, J=9.46 Hz, 1.9H)1.98-2.15 (m, 4.2H) 2.23 (s, 1.2H) 2.39 (s, 0.4H) 2.56-2.72 (m, 1.6H)2.74-2.86 (m, 1.6H) 2.91 (s, 0.8H) 3.47-3.65 (m, 2.8H) 3.74-3.85 (m,1.6H) 3.90 (s, 1.4H) 3.91 (s, 3.1H) 3.93-4.04 (m, 1.8H) 4.19 (d, J=12.82Hz, 0.5H) 4.26 (d, J=14.65 Hz, 0.5H) 4.39 (s, 0.5H) 4.47 (d, J=11.29 Hz,0.4H) 5.18 (s, 0.3H) 5.71-5.92 (m, 1.1H) 7.01 (d, J=2.75 Hz, 0.4H)7.03-7.06 (m, 1.4H) 7.11 (dd, J=8.70, 2.59 Hz, 1.0H) 7.47-7.51 (m, 0.9H)7.52 (s, 0.5H) 7.57 (s, 0.4H) 7.65 (d, J=1.53 Hz, 0.2H) 7.68 (dd,J=8.55, 1.22 Hz, 1.2H) 7.80 (s, 0.6H) 7.80-7.82 (m, 0.7H) 7.84 (s, 0.2H)7.91 (s, 0.4H) 8.04 (s, 0.5H) 8.19 (s, 0.3H) 8.21 (d, J=1.22 Hz, 1.0H)15.15 (d, J=23.80 Hz, 0.4H).

LC-MS retention time 4.21 min (88%); 625 m/z (MH−) and 5.23 min (12%);625 m/z (MH−). LC data was recorded on a Shimadzu LC-10AS liquidchromatograph equipped with a Phenomenex-Luna 10u C18 4.6×50 mm columnusing a SPD-10AV UV-Vis detector at a detector wave length of 220 nM.The elution conditions employed a flow rate of 5 ml/min, a gradient of70% solvent A/30% solvent B to 0% solvent A/100% solvent B, a gradienttime of 5 min, a hold time of 2 min, and an analysis time of 7 min wheresolvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solventB was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data wasdetermined using a Micromass Platform for LC in electrospray.

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[(2E,Z)-3-(dimethylamino)-2-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-oxo-2-propenyl]-3-methoxy-,1,1-dimethylethyl ester

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[3-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-1,3-dioxopropyl]-3-methoxy-,1,1-dimethylethyl ester was dissolved in N,N-Dimethylformamide dimethylacetal (10 mL,). The reaction was fitted with a condenser and placedunder a nitrogen atmosphere. The reaction was heated to reflux for 3hrs, cooled then the volatiles were removed in vacuuo using a rotaryevaporator, then dry in vacuuo at room temperature to obtain the productas an amorphous orange solid (517 mg, 86%).

LC-MS retention time 4.60 min; 682 m/z (MH+). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 4ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 5 min, a hold time of 2 min, and ananalysis time of 7 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode. The intermediate was used without furtherpurification.

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[(2E,Z)-3-(dimethylamino)-2-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-oxo-2-propenyl]-3-methoxy-

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[(2E,Z)-3-(dimethylamino)-2-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-oxo-2-propenyl]-3-methoxy-,1,1-dimethylethyl ester was dissolved in 1,2-dichloroethane (5 mL) andTFA (5 mL) was added to the reaction. The reaction was placed under anitrogen atmosphere and stirred for 2.5 hrs. Volatiles were removed invacuuo from the reaction using a rotary evaporator to give a reddishoil. The product was dissolved in benzene/dichloromethane and thevolatiles again removed in vacuuo to give a red foam. The product wasdissolved in ethyl acetate and washed with 1.0N aqueous hydrochloricacid. The aqueous layer was back extracted with ethyl acetate. Theorganic extracts were combined, washed with brine and dried overmagnesium sulfate. The organic solution was filtered and the volatilesremoved in vacuuo using a rotary evaporator to give a amber-orange foam.The product was dried in vacuuo at room temperature to give 388 mg ofamorphous amber-orange solid.

LC-MS retention time 2.83 min; 624 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 4ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 5 min, a hold time of 2 min, and ananalysis time of 7 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[(2E,Z)-3-(dimethylamino)-2-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-oxo-2-propenyl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

In a 25 ml rb flask, dissolve7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[(2E,Z)-3-(dimethylamino)-2-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-oxo-2-propenyl]-3-methoxy-(385mg, 0.616 mmol) in dichloromethane (6.2 mL), add propane-2-sulfonamide(233 mg, 1.892 mmol) and DMAP (230 mg, 1.880 mmol) to the reactionfollowed by EDC (177 mg, 0.924 mmol). The reaction was placed under anitrogen atmosphere and stirred at room temperature for 18.5 hrs. Thereaction was diluted with ethyl acetate and washed with 1.0N aqueoushydrochloric acid. The aqueous phases were combined and back extractedwith ethyl acetate. The organic layers were combined and sequentiallywashed with 1.0N aqueous hydrochloric acid and brine. The organicsolution was dried over magnesium sulfate, filtered and the solventremoved in vacuuo using a rotary evaporator to give an amorphous orangesolid/foam which was dried in vacuuo to give 415 mg of crude product.

LC-MS retention time 3.00 min; 729 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 5 min, a hold time of 2 min, and ananalysis time of 7 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

The crude product was used without any further purification insubsequent pyrazole synthesis.

The following analog can be prepared using the general methodologydescribed below.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[(2E,Z)-3-(dimethylamino)-2-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-oxo-2-propenyl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-(100mg, 0.137 mmol) in ethanol (547 μL) and dioxane (137 μL). Add thehydrazine reagent (0.146 mmol) followed by TEA (58.2 μL, 0.417 mmol) tothe reaction in a 0.5-2 mL microwave reaction vessel. The vessel wascapped under a nitrogen atmosphere and heated at 160 C for 45 minutes.The reaction was diluted in DMF/Acetonitrile and product compoundpurified by reverse phase HPLC.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-(2-methylpropyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

This compound was isolated using reverse phase HPLC with theinstrumentation listed below using gradient method Bin #16. DionexAPS-3000: Chromeleon 6.70 sp1 LC software; Thermo-Finnigan Xcalibur MSsoftware; Dionex P680 binary pump for analytical; Dionex PP150 binarypump prep; Dionex UVD340U UV spectrometer; Polymer Labs PL-ELS 1000 ELSdetector; Thermo-Finnigen MSQ Surveyor Plus mass spectrometer. LCConditions: Column; Waters Xbridge 19×200 mm 5 um C18; Guard Column;Waters Xbridge 19×10 mm 5 um C18; Mobile Phase; A=Water, 20 mM NH4OH;B=CAN. LC-MS retention time 5.47 min; 756.87 m/z (MH⁺). LC data wasrecorded using Masslynx 4.0 SP4 with a system equipped with: CTC-LeapHTS-PAL autosampler with Harney 4-port injection module, Waters 1525binary pump, Waters 2488 UV detector at 220 nm, Polymer Lab 1000 ELSdetector (evap. Temp.=90 C, Neb. Temp.=80 C) and a Waters LCT massspectrometer with 4 way MUX source. The sample was analyzed using anAscentis 4.6×50 mm 5 uM C18 column. The elution conditions employed aflow rate of 2 ml/min, a gradient of 100% solvent A/0% solvent B to 0%solvent A/100% solvent B, a gradient time of 8 min, a hold time of 1min, and an analysis time of 9 min where solvent A was 5%acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95%acetonitrile/10 mM ammonium acetate. MS ionization using a Waters LCTmass spectrometer in ESI positive mode.

Methyl 1-ethyl-3-methyl-1H-pyrazole-4-carboxylate, and Methyl1-ethyl-5-methyl-1H-pyrazole-4-carboxylate

Methyl 2-((dimethylamino)methylene)-3-oxobutanoate (1.712 g, 10 mmol) inwas suspended in diethyl ether (50 mL), under a nitrogen atmosphere to0° C. Ethylhydrazine oxalate (1.651 g, 11 mmol) in diethyl ether (13mL), triethyl amine (7.0 mL, 50.2 mmol) and ethanol (6 mL) were thenadded. The resultant mixture slowly became more homogeneous and stirringwas continued 0° C. for 40 min, after which the ice bath was removed andthe mixture stirred for an additional 1.5 hours. The reaction was thenpartitioned between ethyl acetate and 1.0N aqueous hydrochloric acid.Extract aqueous phase with ethyl acetate. Combine the organic layers andwash sequentially with 1.0N aqueous hydrochloric acid, saturated aqueoussodium bicarbonate and brine. Dry organic layer over magnesium sulfate,filter and remove volatiles in vacuuo to yield a yellow oil, transfer toa small pear shaped flask in benzene, remove volatiles in vacuuo usingrotary evaporator. The sample was briefly dried in vacuuo on a rotaryevaporator to yield 1.549 g of a yellow liquid/oil.

1H NMR analysis indicated an mixture of isomers of 53:46 ratio.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.32 Hz, 3.01H) 1.46 (t,J=7.32 Hz, 3.56H) 2.44 (s, 3.45H) 2.52 (s, 2.99H) 3.79 (s, 3.49H) 3.79(s, 2.79H) 4.05-4.13 (m, 4.44H) 7.80 (s, 1.09H) 7.82 (s, 0.86H).

LC-MS retention time 0.80 min; 169 m/z (MH+). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

Methyl 1-ethyl-5-iodo-3-methyl-1H-pyrazole-4-carboxylate

In a 100 ml RB a mixture of methyl1-ethyl-3-methyl-1H-pyrazole-4-carboxylate, and methyl1-ethyl-5-methyl-1H-pyrazole-4-carboxylate mixture (1.539 g, 9.15 mmol)was dissolved in anhydrous THF (44 mL). The reaction was placed under anitrogen atmosphere and cooled to −78 C, then n-butyl lithium (5.49 mL,10.98 mmol) 2.0M in pentane was added in a dropwise fashion. The orangesolution at −78 C was then immersed in a acetonitrile/CO2 bath at −44 Cand stirred for 1 hour. The reaction was cooled to −78 C and a solutionof iodine (2.55 g, 10.07 mmol) in tetrahydrofuran (10 mL) was added bycannua over approximately 10 minutes. The reaction was stirred at −78 Cfor 10 minutes after the addition of iodine then the cold bath removedand the reaction allowed to warm to room temperature over 1 hr. Thereaction was quenched with a saturated aqueous solution of ammoniumchloride and extracted into ethyl acetate. The reaction was partitionedbetween ethyl acetate and aqueous saturated ammonium chloride, washedwith aqueous sodium sulfite and again with saturated aqueous ammoniumchloride and brine. The product solution was dried over magnesiumsulfate and volatiles removed in vacuuo using rotary evaporator. Thecrude product was isolated as an amber oil (approx 2.1 g). The titlecompound (Rf=0.66 in 50% ethyl acetate/hexanes on Analtech Uniplatesilica gel GHLF 250 micron TLC plate) was isolated by silica gelchromatography. The crude reaction was adsorbed onto 5.5 g of silica gelusing dichloromethane and chromatographed on 55.9 g of silica gel slurrypacked in a column using 10% ethyl acetate in hexanes. Elution with 10%ethyl acetate in hexanes then a step gradient of 15%, 20%, 25%, 30%,40%, 50% and finally to 70% ethyl acetate in hexanes yielded thepurified product and separation of crude reaction components.

The title compound (424 mg, 30%) was isolated as a nearly colorlesssolid.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.40 (t, J=7.17 Hz, 3H) 2.45 (s,3H) 3.84 (s, 3H) 4.24 (q, J=7.32 Hz, 2H).

LC-MS retention time 1.19 min; 295 m/z (MH+). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[1-ethyl-4-(methoxycarbonyl)-3-methyl-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester

Into a 20 ml microwave vessel charge,7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-(tributylstannyl)-, 1,1-dimethylethyl ester(300 mg, 0.409 mmol), methyl1-ethyl-5-iodo-3-methyl-1H-pyrazole-4-carboxylate (169 mg, 0.573 mmol),bis(triphenylphosphine)palladium(II) dichloride (29.6 mg, 0.042 mmol)and 1 g of activated 3A molecular sieves. Cap reaction vessel andevacuate and fill with nitrogen through three cycles. Dioxane was addedto the reaction and the reagents dissolved at room temperature. Thesealed reaction was heated at 120 C for 17 hrs. Ethyl acetate was addedto the reaction and the reaction filtered through a 0.45 uM Whatmanautovial filter. The filter cake was rinsed with ethyl acetate and thevolatiles were removed from the filtrate in vacuuo to give a 508 mg ofyellow oil. The crude product with an odor of tin was dissolved in 13 mlof dioxane and stirred for 2 hrs with a aqueous solution of potassiumfluoride. An attempt to filter the solution was unsuccessful and theaqueous/organic suspension was poured into a separatory funnel and ethylacetate added and the aqueous layer extracted with ethyl acetate. Theorganic layer was washed with brine and dried over magnesium sulfate,filtered and volatiles removed in vacuuo to obtain 446 mg of amber oilthat still has an odor of tin. The crude product was adsorbed onto 1.1 gof silica gel using dichloromethane and purified on a 15.0 g of silicagel column slurry loaded in dichloromethane. The column was eluted witha step gradient of dichloromethane to 2% ethyl acetate indichloromethane and finally flushed with 5% ethyl acetate indichloromethane. The product fraction were combined and solvent removedin vacuuo to give the title compound (152 mg, 61%) as a amorphous yellowsolid. The compound had a faint odor indicating trace amount of tin maybe present. The product was used in subsequent steps without furtherpurification.

1H NMR shows sample probably contains a butyl tin impurity. 1H NMR (500MHz, CHLOROFORM-D) δ ppm 0.64 (s, 3H) 0.81-0.89 (m, 2H) 0.91 (t, J=7.32Hz, 2.5H, Sn compound?) 1.20-1.31 (m, 7H) 1.31-1.41 (m, 3H) 1.43-1.55(m, 3H) 1.56 (s, 5H) 1.58 (s, 8H) 1.60-1.68 (m, 2H) 1.77 (d, J=9.46 Hz,2H) 1.94 (d, J=7.63 Hz, 1H) 2.03 (s, 0.9H, EtOAc) 2.07 (s, 2H) 2.45 (s,0.4H) 2.47 (s, 3H) 2.53 (s, 0.3H) 2.85 (t, J=11.90 Hz, 1H) 3.50 (d,J=54.93 Hz, 3H) 3.73-3.85 (m, 3H) 3.90 (s, 3H) 4.08-4.14 (m, 0.8H, EtOAcand impurity) 4.59 (q, J=7.22 Hz, 1H) 4.66 (d, J=13.43 Hz, 1H) 4.95 (d,J=14.04 Hz, 1H) 6.72 (s, 1H) 6.92 (d, J=2.44 Hz, 1H) 7.05 (dd, J=8.70,2.59 Hz, 1H) 7.51 (d, J=8.54 Hz, 1H) 7.63 (dd, J=8.55, 1.53 Hz, 1H)7.78-7.83 (m, 1H) 7.85 (s, 1H).

LC-MS retention time 2.74 min; 610 m/z (MH+). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[1-ethyl-4-(methoxycarbonyl)-3-methyl-1H-pyrazol-5-yl]-3-methoxy-

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[1-ethyl-4-(methoxycarbonyl)-3-methyl-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester (151 mg, 0.248 mmol) was dissolved in1,2-dichloroethane (2 ml) and TFA (2.000 ml) added. The reaction wasstirred under a nitrogen atmosphere at room temperature for 2.5 hrs.Volatiles from the reaction were removed in vacuuo using a rotaryevaporator to give a orange/amber oil. The oily product was dissolved ina mixture of dichloromethane and benzene and the volatiles were removedin vacuuo to obtain a yellow amorphous solid. The solid was suspended inbenzene-dichloromethane and again volatiles removed in vacuuo. Theproduct was dried in vacuuo at room temperature to give 151 mg of ayellow solid with a trace odor of tin. The product was triturated withthe addition of 1.5 to 2 mls of dichloromethane and several millilitersof hexanes. The suspension was heated to reflux then allowed to cool.The product as a pale yellow amorphous solid was filtered and rinsedwith hexanes and dried in vacuuo at room temperature to yield 114.7 mgof the title compound.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.60 (s, 3H) 0.88 (t, J=7.02 Hz,1H) 1.19-1.33 (m, 3H) 1.34-1.58 (m, 3H) 1.79 (d, J=8.85 Hz, 2H) 1.96 (s,1H) 2.08 (s, 3H) 2.51 (s, 3H) 2.86 (t, J=11.60 Hz, 1H) 3.41-3.71 (m, 3H)3.73-3.89 (m, 2H) 3.91 (s, 3H) 4.49 (s, 6H) 4.70 (d, J=12.21 Hz, 1H)4.96 (d, J=12.21 Hz, 1H) 6.76 (s, 1H) 6.94 (d, J=2.44 Hz, 1H) 7.08 (dd,J=8.70, 2.59 Hz, 1H) 7.54 (d, J=8.54 Hz, 1H) 7.76 (dd, J=8.39, 1.37 Hz,1H) 7.89 (d, J=8.54 Hz, 1H) 7.95 (s, 1H).

LC-MS retention time 1.87 min; 552 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-ethyl-3-methyl-,methyl ester

7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[1-ethyl-4-(methoxycarbonyl)-3-methyl-1H-pyrazol-5-yl]-3-methoxy-(109.4mg, 0.198 mmol) was suspended in dichloromethane (2 ml) andpropane-2-sulfonamide (82 mg, 0.666 mmol) and DMAP (77.8 mg, 0.637 mmol)were added to the reaction. Upon addition of DMAP the reaction became ahomogeneous yellow solution. EDC (57.7 mg, 0.301 mmol) was added to thereaction and the reaction was capped under a nitrogen atmosphere andstir at room temperature for 2 days. The reaction was diluted with ethylacetate and washed sequentially with 1.0N aqueous hydrochloric acid andbrine. The organic phase was dried over MgSO4, filtered and solventremoved in vacuuo to obtain 128 mg of product as a yellow foam.

1H NMR analysis shows the presence of ethyl acetate and approximately0.24 equivalents of propane-2-sulfonamide reagent. The material was usedwithout further purification.

LC-MS retention time 1.84 min; 657 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.66 (s, 2H) 0.79-0.94 (m, 2H)1.28-1.39 (m, 2H) 1.45-1.49 (m, 6H) 1.50-1.56 (m, 1H) 1.79 (d, J=8.85Hz, 2H) 1.96 (s, 2H) 2.05-2.11 (m, 2H) 2.26 (s, 7H, H2O peak) 2.49 (s, 3H) 2.81-2.91 (m, 1H) 3.38-3.71 (m, 4H) 3.74-3.88 (m, 2H) 3.91 (s, 3H)4.01-4.08 (m, 1H) 4.69 (d, J=15.26 Hz, 1H) 4.94 (d, J=12.51 Hz, 1H) 6.76(s, 1H) 6.94 (d, J=2.75 Hz, 1H) 7.08 (dd, J=8.70, 2.59 Hz, 1H) 7.38 (d,J=8.55 Hz, 1H) 7.53 (d, J=8.55 Hz, 1H) 7.76 (s, 1H) 7.89 (d, J=8.54 Hz,1H) 8.30 (s, 1H).

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-1-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-ethyl-3-methyl-

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-ethyl-3-methyl-,methyl ester (127 mg, 0.193 mmol) was dissolved in THF (3 ml) andmethanol (3 ml) added to the solution. Sodium hydroxide (3 ml, 3.00mmol, 1.0N aqueous solution) was added to the homogeneous yellowsolution reaction. The reaction turned to a rose-reddish cloudy colorafter complete addition of sodium hydroxide solution. The reaction wasstirred at room temperature under a nitrogen atmosphere and eventuallybecame a clear rose colored solution. The reaction was stirred at roomtemperature under a nitrogen atmosphere. HPLC analysis after 40 hoursrevealed 78% conversion to product. Sodium hydroxide (1.0 ml, 1.00 mmol,1.0N aqueous solution) was added to the reaction and the reactionstirred under a nitrogen atmosphere for an additional 24 hrs. Thereaction was concentrated to dryness in vacuuo using a rotary evaporatorwith bath at ambient temperature. The pink solid residue was partitionedbetween ethyl acetate and 1.0N aqueous hydrochloric acid. The aqueousphase was extracted with ethyl acetate and the organic layers combinedand washed sequentially with 1.0N aqueous hydrochloric acid and brine.The organic layer was dried over magnesium sulfate, filtered andsolvents removed in vacuuo to give a yellow solid which was dried invacuuo at room temperature to give 108 mg of the title compound as aamorphous yellow solid.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.71 (s, 3H) 0.81-0.94 (m, 2H)0.96-1.20 (m, 3H) 1.23-1.27 (m, 3H) 1.27-1.37 (m, 3H) 1.41 (t, J=7.17Hz, 6H) 1.45-1.53 (m, 2H) 1.60-1.73 (m, 1H) 1.77 (d, J=11.90 Hz, 2H)1.86-2.02 (m, 2H) 2.04-2.08 (m, 1H) 2.47 (s, 2H) 2.77-2.89 (m, 1H)3.43-3.69 (m, 4H) 3.70-3.86 (m, 2H) 3.99-4.06 (m, 2H) 4.61 (d, J=10.07Hz, 1H) 4.95 (d, J=13.73 Hz, 1H) 6.75 (s, 1H) 6.94 (d, J=2.44 Hz, 1H)7.03-7.10 (m, 1H) 7.42 (d, J=8.24 Hz, 1H) 7.47-7.54 (m, 1H) 7.79-7.91(m, 2H) 8.76 (s, 1H).

LC-MS retention time 1.50 min; 643 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-ethyl-3-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-ethyl-3-methyl-(61.1mg, 0.095 mmol) was dissolved in DMF (948 μL) and HATU (80 mg, 0.210mmol) added to the reaction. The reaction was capped under a nitrogenatmosphere and stirred at room temperature for 1 hr. DMAP (36.7 mg,0.300 mmol) was added to the reaction followed by the amine reagent,(2R,6S)-2,6-dimethylmorpholine (35.2 μL, 0.284 mmol). The clear yellowreaction solution was capped under a nitrogen atmosphere and thereaction stirred at room temperature for 42 hours. The product waspurified on a Shimadzu high pressure liquid chromatography systememploying Discovery VP software interfaced with a SCL-10A controller,SIL-10A autosampler and FRC-10A fraction collector. The reaction wasdiluted to 2 ml with acetonitrile purified using a Waters Sunfire PrepC18 OBD, 5 uM 19 mm×150 mm column and monitored using a SPD-10AV UV-Visdetector at a detector wave length of 220 nM. The elution conditionsemployed a flow rate of 25 mL/min, a gradient of 50% solvent A/50%solvent B to 0% solvent A/100% solvent B, a gradient time of 25 minuteswith a run time of 30 minutes using % A=10% acetonitrile, 90% water,0.1% TFA % B=90% acetonitrile, 10% water, 0.1% TFA solvent system.Retention time of product was from 16.16 to 17.47 minutes. The productfractions were combined and volatiles removed in vacuuo using a rotaryevaporator. The title compound was dried in vacuuo at room temperatureto yield 36.3 mg as a yellow amorphous solid.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.68 (s, 4H) 0.75-0.93 (m, 2H) 1.05(s, 1H) 1.30-1.45 (m, 6H) 1.51 (dd, J=21.82, 6.26 Hz, 7H) 1.79 (d,J=10.68 Hz, 2H) 1.89-2.02 (m, 3H) 2.03-2.16 (m, 3H) 2.26 (s, 12H) 2.88(t, J=10.68 Hz, 1H) 2.95-3.31 (m, 3H) 3.34-3.75 (m, 1H) 3.94 (s, 3H)4.03-4.11 (m, 1H) 4.17 (s, 2H) 4.57 (d, J=14.65 Hz, 1H) 4.87 (d, J=15.56Hz, 1H) 6.74-6.86 (m, 1H) 6.93 (s, 1H) 7.12 (d, J=7.02 Hz, 1H) 7.58 (d,J=8.54 Hz, 1H) 7.66 (s, 1H) 7.73 (s, 1H) 7.90 (d, J=8.24 Hz, 1H) 10.66(s, 1H).

LC-MS retention time 1.93 min; 740 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-ethyl-3-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-

1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-ethyl-3-methyl-(45.8mg, 0.071 mmol) was dissolved DMF (710 μL) and HATU (62.7 mg, 0.165mmol) was added to the reaction. The reaction was capped under anitrogen atmosphere and stirred for 1 hr at room temperature. DMAP (37.1mg, 0.304 mmol), was added to the reaction followed by the amine reagent8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (23.3 mg, 0.156 mmol). Thereaction was again capped under a nitrogen atmosphere and stirred atroom temperature for 42 hrs. The product was purified on a Shimadzu highpressure liquid chromatography system employing Discovery VP softwareinterfaced with a SCL-10A controller, SIL-10A autosampler and FRC-10Afraction collector. The reaction was diluted to 2 ml with acetonitrilepurified using a Waters Sunfire Prep C18 OBD, 5 uM 19 mm×150 mm columnand monitored using a SPD-10AV UV-Vis detector at a detector wave lengthof 220 nM. The elution conditions employed a flow rate of 25 mL/min, agradient of 50% solvent A/50% solvent B to 0% solvent A/100% solvent B,a gradient time of 25 minutes with a run time of 35 minutes using %A=10% acetonitrile, 90% water, 0.1% TFA % B=90% acetonitrile, 10% water,0.1% TFA solvent system. Retention time of product was from 14.77 to15.57 minutes. Volatiles were removed from the product fraction invacuuo using a rotary evaporator. The title compound was dried in vacuuoat room temperature to yield 28.2 mg of a yellow amorphous solid.

1H NMR (500 MHz, CHLOROFORM-D) δ ppm 0.68 (s, 1H) 1.14-1.30 (m, 2H)1.32-1.55 (m, 11H) 1.55-1.72 (m, 3H) 1.80 (t, J=10.68 Hz, 2H) 1.90-1.30(m, 2H) 2.11 (s, 12H) 2.19-2.34 (m, 4H) 2.85 (t, J=11.75 Hz, 1H) 2.98(d, J=11.90 Hz, 1H) 3.13 (s, 1H) 3.25-3.68 (m, 2H) 3.74-3.91 (m, 2H)3.94 (s, 3H) 4.00-4.10 (m, 1H) 4.19 (d, J=27.77 Hz, 2H) 4.55 (d, J=14.95Hz, 1H) 4.80 (d, J=14.65 Hz, 1H) 5.03 (s, 0.15H) 6.82 (s, 1H) 6.93 (s,1H) 7.11 (dd, J=8.70, 2.59 Hz, 1H) 7.54 (d, J=8.55 Hz, 1H) 7.62 (d,J=7.63 Hz, 2H) 7.81-8.01 (m, 1H) 10.51 (s, 1H).

LC-MS retention time 1.79 min; 738 m/z (MH−). LC data was recorded on aShimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna10u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detectorwave length of 220 nM. The elution conditions employed a flow rate of 5ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100%solvent B, a gradient time of 3 min, a hold time of 1 min, and ananalysis time of 4 min where solvent A was 5% acetonitrile/95% H2O/10 mMammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mMammonium acetate. MS data was determined using a Micromass Platform forLC in electrospray mode.

7H-indolo[2,1-a][2]benzazepine-6-propanoic acid,13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-beta-oxo-,ethyl ester

To a stirred solution of 7H-indolo[2,1-a][2]benzazepine-6-carboxylicacid,13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-(4g, 7.45 mmol) in THF (20 mL) was added CDI (1.151 g, 7.10 mmol) and themixture was heated at 45° C. for 0.5 h and the reaction mixture wascooled and transferred into a suspension of magnesium chloride (1.419 g,14.91 mmol) and potassium ethyl malonate (2.54 g, 14.91 mmol) in THF (15mL). Additional THF (40 mL) was added to dissolve the ensuingprecipitation. The reaction mixture was stirred for 0.5 h at r. t. andthen heated at 60° C. overnight. R×n mixture was cooled to rt anddiluted with EtOAc, washed with 1N HCl, brine and dried (Mg2SO4). Crudeproduct was purified on a Thomson 160 g column (MeOH/DCM: 0 to 25%) toafford the product as a reddish solid (3.8 g, 84%). LC/MS method: Start% B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flowrate: 4 mL/min; Wavelength: 220 Solvent A: 10% MeOH/90% H₂O/0.1%Trifluoroacetic Acid; Solvent B: 10% H₂O/90% MeOH/0.1% TrifluoroaceticAcid; Column: XBridge 4.6×50 mm S5.

LC/MS: retention time 3.418 min, m/z 607 (MH⁺).

1H-pyrrole-3-carboxylic acid,2-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(1-methylethyl)-,ethyl ester

To a solution of 7H-indolo[2,1-a][2]benzazepine-6-propanoic acid,13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-beta-oxo-,ethyl ester (0.8 g, 1.055 mmol) in THF (3 mL) was added propan-2-amine(0.624 g, 10.55 mmol) and Tosic Acid (10.03 mg, 0.053 mmol). The mixturewas stirred at r.t. for 0.5 h and 1,2-dibromoethyl acetate (0.337 g,1.371 mmol) was added at 0° C. The reaction mixture was stirred at r.t.for 0.5 h and then sodium hydride (0.051 g, 2.110 mmol) was added andstirred for 10 min at r.t. The mixture was heated at 60° C. for 3 h andcooled to r.t., diluted with EtOAc and washed with ice cold HCl (1N),brine and dried (MgSO4). Crude product was purified on a Biotage 25Mcolumn, (EtOAc/hexane: 5-100%) to afford the compound as a beige foam(0.26 g, 35%). LC/MS method: Start % B: 0; Final % B: 100; Gradienttime: 3 min; Stop time: 4 min; Flow rate: 4 mL/min; Wavelength: 220Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid; Solvent B: 10%H₂O/90% MeOH/0.1% Trifluoroacetic Acid; Column: XBridge 4.6×50 mm S5.LC/MS: retention time 3.631 min, m/z 672 (MH⁺).

1H-pyrrole-3-carboxylic acid,2-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(1-methylethyl)-

To a solution of 1H-pyrrole-3-carboxylic acid,2-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6yl]-1-(1-methylethyl)-,ethyl ester (80 mg, 0.119 mmol) in THF (2 mL) and was added potassiumtrimethylsilanolate (45.8 mg, 0.357 mmol). The mixture was stirred undernitrogen for 30 min and another portion of potassium trimethylsilanolate(100 mg) was added. The reaction mixture was stirred at r.t. for 2 daysand diluted with EtOAc, washed with cold 1 N HCl, brine, dried (MgSO4)and removed the solvent to afford the acid as a beige solid (71 mg,88%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.80 (1H, br. s.), 7.81-7.89(1H, m), 7.76 (1H, s), 7.45-7.52 (1H, m), 7.42 (1H, d, J=6.29 Hz), 7.03(1H, dd, J=8.69, 2.64 Hz), 6.93 (1H) d, J=2.27 Hz), 6.47-6.76 (3H, m),4.98 (1H, d, J=13.85 Hz), 4.61 (1H, d, J=14.60 Hz), 3.97-4.07 (1H, m),3.89 (1H, s), 3.34-3.52 (1H, m), 2.73-2.89 (1H, m), 1.87-2.12 (4H, m),1.66-1.84 (2H, m), 0.81-1.55 (19H, m). LC/MS method: Start % B: 0; Final% B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 mL/min;Wavelength: 220 Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid;Solvent B: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid; Column: XBridge4.6×50 mm S5. LC/MS: retention time 3.503 min, m/z 644 (MH⁺).

13-Cyclohexyl-6-(1-isopropyl-3-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)-1H-pyrrol-2-yl)-3-methoxy-N-(isopropylsulfonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.87 (1H, d, J=8.56 Hz), 7.78 (1H,s), 7.66 (1H, d, J=8.06 Hz), 7.54 (1H, d, J=8.31 Hz), 7.02-7.09 (1H, m),6.89 (1H, d, J=2.77 Hz), 6.83 (1H, br. s.), 6.69 (1H, br. s.), 6.48 (1H,br. s.), 4.91 (1H, d, J=15.36 Hz), 4.55 (1H, d, J=15.61 Hz), 4.48 (1H,br. s.), 4.01-4.13 (1 H, m), 3.93 (3H, s), 3.58 (1H, br. s.), 3.12 (1H,br. s.), 2.78-2.92 (1H, m), 1.70-2.34 (14H, m), 1.13-1.68 (16H, m), 1.05(1H, br. s.), 0.52 (1H, br. s.), −0.30 (1H, br. s.). LC/MS method: Start% B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flowrate: 4 mL/min; Wavelength: 220 Solvent A: 10% MeOH/90% H₂O/0.1%Trifluoroacetic Acid; Solvent B: 10% H₂O/90% MeOH/0.1% TrifluoroaceticAcid; Column: XBridge 4.6×50 mm S5. LC/MS: retention time 3.331 min, m/z752 (MH⁺).

13-Cyclohexyl-6-(1-isopropyl-3-(4-propylpiperazine-1-carbonyl)-1H-pyrrol-2-yl)-3-methoxy-N-(isopropylsulfonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.87 (1H, d, J=8.56 Hz), 7.79 (1H,s), 7.59 (1H, d, J=8.31 Hz), 7.53 (1H, d, J=8.56 Hz), 7.05 (1H, dd,J=8.69, 2.64 Hz), 6.90 (1H, d, J=2.52 Hz), 6.78 (1H, br. s.), 6.68 (1H,s), 6.32 (1H, d, J=2.27 Hz), 4.91 (1H, d, J=14.60 Hz), 4.55 (2H, d,J=14.86 Hz), 3.99-4.50 (2H, m), 3.95-4.32 (1H, m), 3.92 (3H, s),2.70-3.19 (5H, m), 1.86-2.16 (8H, m), 1.67-1.84 (2H, m), 1.09-1.64 (18H,m), 0.65-0.83 (3H, m). LC/MS method: Start % B: 0; Final % B: 100;Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 mL/min; Wavelength:220 Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid; Solvent B:10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid; Column: XBridge 4.6×50 mmS5. LC/MS: retention time 3.330 min, m/z 754 (MH⁺).

13-Cyclohexyl-6-(3-((2S,6R)-2,6-dimethylmorpholine-4-carbonyl)-1-isopropyl-1H-pyrrol-2-yl)-3-methoxy-N-(isopropylsulfonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.87-7.93 (1H, m), 7.75 (1H, br.s.), 7.44-7.66 (2H, m), 7.01-7.12 (1H, m), 6.90 (1H, br. s.), 6.83 (1H,br. s.), 6.64 (1H, br. s.), 6.37 (1H, br. s.), 4.90 (0H, d, J=14.86 Hz),4.57 (1H, s), 4.31-4.50 (1H, m), 4.05-4.16 (1H, m), 3.94 (3H, s),3.85-3.92 (1H, m), 2.70-3.74 (5H, m), 1.84-2.25 (7H, m), 1.66-1.84 (2H,m), 0.97-1.66 (20H, m), 0.53-0.93 (5H, m); LC/MS method: Start % B: 0;Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4mL/min; Wavelength: 220 Solvent A: 10% MeOH/90% H₂O/0.1% TrifluoroaceticAcid; Solvent B: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid; Column:XBridge 4.6×50 mm S5.

LC/MS: retention time 3.550 min, m/z 741 (MH⁺).

13-Cyclohexyl-6-(1-isopropyl-3-(morpholine-4-carbonyl)-1H-pyrrol-2-yl)-3-methoxy-N-(isopropylsulfonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.21 (1H, br. s.), 7.92 (1H, d,J=8.56 Hz), 7.84 (1H, s), 7.61 (1H, d, J=8.31 Hz), 7.56 (1H, d, J=8.81Hz), 7.09 (1H, dd, J=8.69, 2.64 Hz), 6.90 (1H, d, J=2.77 Hz), 6.82 (1H,br. s.), 6.69 (1H, s), 6.36 (1H, d, J=2.52 Hz), 4.94 (1H, d, J=14.86Hz), 4.56 (1H, d, J=15.11 Hz), 4.38 (1H, br. s.), 4.02-4.12 (1H, m),3.94 (3H, s), 3.58-4.14 (2H, m), 2.53-3.28 (6H, m), 1.95 (1H, br. s.),1.88-2.30 (4H, m), 1.72-1.85 (2H, m), 1.08-1.64 (16H, m).

3-Furancarboxylic acid,2-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-,ethyl ester

1H-pyrrole-3-carboxylic acid,2-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-,ethyl ester

To a solution of starting 7H-indolo[2,1-a][2]benzazepine-6-propanoicacid,13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-beta-oxo-,ethyl ester (1.200 g, 1.978 mmol) in THF (20 mL) was added1,2-dibromoethyl acetate in THF (0.26 M, 9.13 mL, 2.373 mmol). NH₃ wasthen bubbled through the mixture for 10 min and the reaction wasmaintained under ammonia (1 atmosphere) overnight. The mixture was thenheated at 60° C. for 2 h and then cooled to room temperature, dilutedwith EtOAc and washed with cold 0.5 N HCl (3×) and brine. The organiclayer was then dried (MgSO₄) and filtered and the filtrate evaporatedunder reduced pressure. The crude product was purified on a Biotage 40MColumn (EtOAc/hexane 0% to 100%) to afford a yellow solid which wasfurther purified by preparative HPLC to afford the title furan (65 mg,5%) and title pyrrole (145 mg, 11%). Furan product: 1H NMR (400 MHz,METHANOL-d₄) δ ppm 8.10 (1H, s), 7.90 (1H, d, J=8.56 Hz), 7.81 (1H, s),7.49-7.63 (3H, m), 7.05-7.18 (2 H, m), 6.86 (1H, d, J=2.01 Hz), 5.93(1H, d, J=14.35 Hz), 4.28-4.47 (3H, m), 3.94-4.02 (1H, m), 3.92 (3H, s),2.79-2.96 (1H, m), 1.86-2.23 (4H, m), 1.69-1.84 (2H, m), 1.44 (6H, d,J=6.80 Hz), 1.35 (3H, t, J=7.05 Hz), 1.27-1.60 (4H, m). LC/MS method:Start % B: 0; Final % B: 100; Gradient time: 3 min; Stop time: 4 min;Flow rate: 4 mL/min; Wavelength: 220 Solvent A: 10% MeOH/90% H₂O/0.1%Trifluoroacetic Acid; Solvent B: 10% H₂O/90% MeOH/0.1% TrifluoroaceticAcid; Column: XBridge 4.6×50 mm S5. LC/MS: retention time 3.736 min, m/z631 (MH⁺). Pyrrole product: 1H NMR (400 MHz, MeOD) δ ppm 11.02 (1H, br.s.), 8.03 (1H, br. s.), 7.84 (1H, d, J=8.56 Hz), 7.81 (1H, s), 7.47-7.56(2H, m), 7.01-7.11 (2H, m), 6.90 (1H, s), 6.58-6.64 (2H, m), 5.44 (1H,d, J=17.63 Hz), 4.51 (1H, d, J=14.10 Hz), 4.18-4.35 (2H, m), 3.87 (3H,s), 3.81-3.97 (1H, m), 2.82-2.95 (1 H, m), 1.86-2.20 (4H, m), 1.68-1.84(2H, m), 1.12-1.55 (13H, m). LC/MS method: Start % B: 0; Final % B: 100;Gradient time: 3 min; Stop time: 4 min; Flow rate: 4 mL/min; Wavelength:220 Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid; Solvent B:10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid; Column: XBridge 4.6×50 mmS5. LC/MS: retention time 3.475 min, m/z 630 (MH⁺).

3-Furancarboxylic acid,2-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-

To a mixture of 3-Furancarboxylic acid,2-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-,ethyl ester (63 mg, 0.100 mmol) and potassium trimethylsilanolate (128mg, 0.999 mmol) was added THF (2 mL). The mixture was stirred at r. t.under nitrogen for 2 h. Diluted with EtOAc and washed with cold 1N HCland dried (MgSO4), removed the solvents to afford acid (48 mg, 80%).LC/MS method: Start % B: 0; Final % B: 100; Gradient time: 3 min; Stoptime: 4 min; Flow rate: 4 mL/min; Wavelength: 220 Solvent A: 10%MeOH/90% H₂O/0.1% Trifluoroacetic Acid; Solvent B: 10% H₂O/90% MeOH/0.1%Trifluoroacetic Acid; Column: XBridge 4.6×50 mm S5.

LC/MS: retention time 3.558 min, m/z 603 (MH⁺).

13-cyclohexyl-6-(3-(morpholine-4-carbonyl)furan-2-yl)-3-methoxy-N-(isopropylsulfonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.08 (1H, d, J=1.01 Hz), 7.86 (1H,d, J=8.56 Hz), 7.66 (1H, dd, J=8.44, 1.38 Hz), 7.49 (1H, d, J=8.56 Hz),7.40 (1H, d, J=1.76 Hz), 7.33 (1H, s), 7.04 (1H, dd, J=8.56, 2.77 Hz),6.96 (1H, d, J=2.52 Hz), 6.48 (1H, d), 5.23 (1H, d), 4.40 (1H, d),3.99-4.18 (2H, m), 3.90 (3 H, s), 3.79-3.95 (1H, m), 3.67-3.78 (2H, m),3.42-3.51 (2H, m), 3.33-3.41 (1 H, m), 3.19-3.31 (1H, m), 2.75-2.88 (1H,m), 1.86-2.13 (4H, m), 1.14-1.83 (12 H, m); LC/MS method: Start % B: 0;Final % B: 100; Gradient time: 3 min; Stop time: 4 min; Flow rate: 4mL/min; Wavelength: 220 Solvent A: 10% MeOH/90% H₂O/0.1% TrifluoroaceticAcid; Solvent B: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid; Column:XBridge 4.6×50 mm S5. LC/MS: retention time 3.276 min, m/z 711 (MH⁺).

13-cyclohexyl-6-(3-(3-methyl-3,8-diazabicyclo[3.2.1]octane-8-carbonyl)furan-2-yl)-1H-pyrrol-2-yl)-3-methoxy-N-(isopropylsulfonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide.LC/MS method: Start % B: 0; Final % B: 100; Gradient time: 3 min; Stoptime: 4 min; Flow rate: 4 mL/min; Wavelength: 220 Solvent A: 10%MeOH/90% H₂O/0.1% Trifluoroacetic Acid; Solvent B: 10% H₂O/90% MeOH/0.1%Trifluoroacetic Acid; Column: XBridge 4.6×50 mm S5.

LC/MS: retention time 3.503 min, m/z 644 (MH⁺).

5H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[3-[(dimethylamino)carbonyl]-5-methyl-4H-1,2,4-triazol-4-yl]-N-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-

To a mixture of ethanediamide,N′-[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-6,7-dihydro-3-methoxy-5H-indolo[2,1-a][2]benzazepin-6-yl]-N,N-dimethyl-(19.9mg, 0.033 mmol) in CH₂Cl₂ (1 mL) at 0° C. under N₂ was added phosphoruspentachloride (20.4 mg, 0.098 mmol). The mixture was stirred at 0° C.for 2 hours, and then added with acetylhydrazine (7.25 mg, 0.098 mmol).The mixture was stirred at 0° C. for 1 hour, and then at r.t. for 21hours. The mixture was added another 14.5 mg (0.196 mmol) ofacetylhydrazine, evaporated to dryness, added PhCH₃ (1 mL), and thenstirred at 120° C. for 6 hours. The mixture was cooled to r.t. and thenevaporated. The residue was diluted with MeOH and purified by usingShimadzu-VP preparative reverse phase HPLC to obtain the TFA salt of theproduct using the separation method: Solvent A=10% MeOH-90% H₂O-0.1%TFA, Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=60, Final % B=90,Gradient time=10 min, Stop time=12 min, Flow Rate=30 mL/min, Column:Xterra Prep MS C18 5 u 30×50 mm, Fraction Collection: 7.02-7.62 min. (UVdetection at 220 nm). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm;(ES+) m/z (M+H)⁺=648.41, HPLC R_(t)=1.787 min. HPLC method: Solvent A=5%MeCN-95% H₂O-10 mM NH₄OAc, Solvent B=95% MeCN-5% H₂O-10 mM NH₄OAc, Start% B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5ml/min, Column: Phenomenex Lina C18 5 um 3.0×50 mm; (ES+) m/z(M+H)⁺=648.38, HPLC R_(t)=1.260 min. Analytical HPLC were performed byusing Shimadzu-VP instrument with UV detection at 254 nm and 256 nm.Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA, SolventB=95% MeCN-5% H₂O-0.1% TFA, Start % B=10, Final % B=100, Gradienttime=10 min, Stop time=20 min, Flow Rate=1 ml/min, Column: WatersSunfire C-18, 4.6×150 mm, 3.5 um; R_(t)=10.46 min; Column: WatersXbridge Phenyl 4.6×150 mm, 3.5 um; R_(t)=9.42 min.

5H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[3-[(dimethylamino)carbonyl]-4H-1,2,4-triazol-4-yl]-N-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-

This example was prepared in a similar manner as described by usingformylhydrazine as the coupling partner. Purification by Shimadzu-VPpreparative reverse phase HPLC to obtain the TFA salt of the productusing the separation method: Solvent A=10% MeOH-90% H₂O-0.1% TFA,Solvent B=90% MeOH-10% H₂O-0.1% TFA, Start % B=40, Final % B=90,Gradient time=10 min, Stop time=12 min, Flow Rate=30 mL/min, Column:Xterra Prep MS C18 5 u 30×50 mm, Fraction Collection: 9.57-9.99 min. (UVdetection at 220 nm). LC/MS were performed by using Shimadzu-VPinstrument with UV detection at 220 nm and Waters Micromass. HPLCmethod: Solvent A=10% MeOH-90% H₂O-0.1% TFA, Solvent B=90% MeOH-10%H₂O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stoptime=3 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm;(ES+) m/z (M+H)⁺=634.45, HPLC R_(t)=1.785 min. Analytical HPLC wereperformed by using Shimadzu-VP instrument with UV detection at 254 nmand 256 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H₂O-0.1% TFA,Solvent B=95% MeCN-5% H₂O-0.1% TFA, Start % B=10, Final % B=100,Gradient time=10 min, Stop time=20 min, Flow Rate=1 ml/min, Column:Waters Sunfire C-18, 4.6×150 mm, 3.5 um; R_(t)=10.33 min; Column: WatersXbridge Phenyl 4.6×150 mm, 3.5 um; R_(t)=9.44 min.

Biological Methods

The compounds demonstrated activity against HCV NS5B as determined inthe following HCV RdRp assays.

HCV NS5B RdRp cloning, expression, and purification. The cDNA encodingthe NS5B protein of HCV, genotype 1b, was cloned into the pET21aexpression vector. The protein was expressed with an 18 amino acidC-terminal truncation to enhance the solubility. The E. coli competentcell line BL21(DE3) was used for expression of the protein. Cultureswere grown at 37° C. for ˜4 hours until the cultures reached an opticaldensity of 2.0 at 600 nm. The cultures were cooled to 20° C. and inducedwith 1 mM IPTG. Fresh ampicillin was added to a final concentration of50 μg/ml and the cells were grown overnight at 20° C.

Cell pellets (3 L) were lysed for purification to yield 15-24 mgs ofpurified NS5B. The lysis buffer consisted of 20 mM Tris-HCl, pH 7.4, 500mM NaCl, 0.5% triton X-100, 1 mM DTT, 1 mM EDTA, 20% glycerol, 0.5 mg/mllysozyme, 10 mM MgCl2, 15 ug/ml deoxyribonuclease I, and Complete™protease inhibitor tablets (Roche). After addition of the lysis buffer,frozen cell pellets were resuspended using a tissue homogenizer. Toreduce the viscosity of the sample, aliquots of the lysate weresonicated on ice using a microtip attached to a Branson sonicator. Thesonicated lysate was centrifuged at 100,000×g for 1 hr at 4° C. andfiltered through a 0.2 μm filter unit (Corning).

The protein was purified using three sequential chromatography steps:Heparin sepharose CL-6B, polyU sepharose 4B, and Hitrap SP sepharose(Pharmacia). The chromatography buffers were identical to the lysisbuffer but contained no lysozyme, deoxyribonuclease I, MgCl2 or proteaseinhibitor and the NaCl concentration of the buffer was adjustedaccording to the requirements for charging the protein onto the column.Each column was eluted with a NaCl gradient which varied in length from5-50 column volumes depending on the column type. After the finalchromatography step, the resulting purity of the enzyme is >90% based onSDS-PAGE analysis. The enzyme was aliquoted and stored at −80° C.

Standard HCVNS5B RdRp enzyme assay. HCV RdRp genotype 1b assays were runin a final volume of 60 μl in 96 well plates (Costar 3912). The assaybuffer is composed of 20 mM Hepes, pH 7.5, 2.5 mM KCl, 2.5 mM MgCl2, 1mM DTT, 1.6 U RNAse inhibitor (Promega N2515), 0.1 mg/ml BSA (PromegaR3961), and 2% glycerol. All compounds were serially diluted (3-fold) inDMSO and diluted further in water such that the final concentration ofDMSO in the assay was 2%. HCV RdRp genotype 1b enzyme was used at afinal concentration of 28 nM. A polyA template was used at 6 nM, and abiotinylated oligo-dT12 primer was used at 180 nM final concentration.Template was obtained commercially (Amersham 27-4110). Biotinylatedprimer was prepared by Sigma Genosys. 3H-UTP was used at 0.6 μCi (0.29μM total UTP). Reactions were initiated by the addition of enzyme,incubated at 30° C. for 60 min, and stopped by adding 25 μl of 50 mMEDTA containing SPA beads (4 μg/μl, Amersham RPNQ 0007). Plates wereread on a Packard Top Count NXT after >1 hr incubation at roomtemperature.

Modified HCV NS5B RdRp enzyme assay. A modified enzyme assay wasperformed essentially as described for the standard enzyme assay exceptfor the following: The biotinylated oligo dT12 primer was precaptured onstreptavidin-coated SPA beads by mixing primer and beads in assay bufferand incubating at room temperature for one hour. Unbound primer wasremoved after centrifugation. The primer-bound beads were resuspended in20 mM Hepes buffer, pH 7.5 and used in the assay at final concentrationsof 20 nM primer and 0.67 μg/μl beads. Order of addition in the assay:enzyme (14 nM) was added to diluted compound followed by the addition ofa mixture of template (0.2 nM), 3H-UTP (0.6 μCi, 0.29 μM), andprimer-bound beads, to initiate the reaction; concentrations given arefinal. Reactions were allowed to proceed for 4 hours at 30° C.

IC₅₀ values for compounds were determined using seven different [I].IC₅₀ values were calculated from the inhibition using the formulay=A+((B−A)/(1+((C/x)^D))).

FRET Assay Preparation. To perform the HCV FRET screening assay, 96-wellcell culture plates were used. The FRET peptide (Anaspec, Inc.) (Talianiet al., Anal. Biochem. 1996, 240, 60-67) contains a fluorescence donor,EDANS, near one end of the peptide and an acceptor, DABCYL, near theother end. The fluorescence of the peptide is quenched by intermolecularresonance energy transfer (RET) between the donor and the acceptor, butas the NS3 protease cleaves the peptide the products are released fromRET quenching and the fluorescence of the donor becomes apparent. Theassay reagent was made as follows: 5× cell Luciferase cell culture lysisreagent from Promega (#E153A) diluted to 1× with dH₂O, NaCl added to 150mM final, the FRET peptide diluted to 20 μM final from a 2 mM stock.

To prepare plates, HCV replicon cells, with or without a Renillaluciferase reporter gene, were trypsinized and placed into each well ofa 96-well plate with titrated test compounds added in columns 3 through12; columns 1 and 2 contained a control compound (HCV proteaseinhibitor), and the bottom row contained cells without compound. Theplates were then placed in a CO₂ incubator at 37° C.

Assays. Subsequent to addition of the test compounds described above(FRET Assay Preparation), at various times the plate was removed andAlamar blue solution (Trek Diagnostics, #00-100) was added per well as ameasure of cellular toxicity. After reading in a Cytoflour 4000instrument (PE Biosystems), plates were rinsed with PBS and then usedfor FRET assay by the addition of 30 ul of the FRET peptide assayreagent described above (FRET Assay Preparation) per well. The plate wasthen placed into the Cytoflour 4000 instrument which had been set to 340excite/490 emission, automatic mode for 20 cycles and the plate read ina kinetic mode. Typically, the signal to noise using an endpointanalysis after the reads was at least three-fold. Alternatively, afterAlamar blue reading, plates were rinsed with PBS, 50 ul of DMEM (highglucose) without phenol red was added and plates were then used forluciferase assay using the Promega Dual-Glo Luciferase Assay System.

Compound analysis was determined by quantification of the relative HCVreplicon inhibition and the relative cytotoxicity values. To calculatecytoxicity values, the average Alamar Blue fluorescence signals from thecontrol wells were set as 100% non-toxic. The individual signals in eachof the compound test wells were then divided by the average controlsignal and multiplied by 100% to determine percent cytotoxicity. Tocalculate the HCV replicon inhibition values, an average backgroundvalue was obtained from the two wells containing the highest amount ofHCV protease inhibitor at the end of the assay period. These numberswere similar to those obtained from naïve Huh-7 cells.

The background numbers were then subtracted from the average signalobtained from the control wells and this number was used as 100%activity. The individual signals in each of the compound test wells werethen divided by the averaged control values after background subtractionand multiplied by 100% to determine percent activity. EC₅₀ values for aprotease inhibitor titration were calculated as the concentration whichcaused a 50% reduction in FRET or luciferase activity. The two numbersgenerated for the compound plate, percent cytoxicity and percentactivity were used to determine compounds of interest for furtheranalysis.

Representative data for some compounds are reported in Table 1.

TABLE 1 Structure IC₅₀ (μM) EC₅₀ (μM)

B B

B B

B B

B B

B B

A B

B B

B B

D D

D D

B D

B B

B B

D D

B B

B B

B B

B B

B B

B B

B B

B B

A B

B B

B B

D B

B B

B B

B

B B

C B

B B

C B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B A

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B

B

B

B

B B

B

B B

B

B

B

B

B B

B B

B B

B

B

B B

B B

B B

B B

B B

B

B

B B

B B

B

B B

B B

B

B

B

B B

B B

B B

B

B B

B B

B

B B

B

B B

B B

B B

B B

B B

B B

B B

B D

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B

B

B B

B D

B B

B B

B A

B B

B B

B B

B A

B B

B B

B B

B B

B A

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

C B

C B

B B

B B

B B

B B

B B

B B

B B

C B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B

B B A >0.5 μM; B 0.001 μM-0.5 μM; C <0.02 μM but an exact value was notdetermined; D >0.04 μM; but an exact value was not determined.

Pharmaceutical Compositions and Methods of Treatment

The compounds demonstrate activity against HCV NS5B and can be useful intreating HCV and HCV infection. Therefore, another aspect of theinvention is a composition comprising a compound, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a composition further comprising acompound having anti-HCV activity.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is an interferon. Another aspect of theinvention is where the interferon is selected from interferon alpha 2B,pegylated interferon alpha, consensus interferon, interferon alpha 2A,and lymphoblastoid interferon tau.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is a cyclosporin. Another aspect of theinvention is where the cyclosporin is cyclosporin A.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is selected from the group consisting ofinterleukin 2, interleukin 6, interleukin 12, a compound that enhancesthe development of a type 1 helper T cell response, interfering RNA,anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophosphatedehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is a composition where the compoundhaving anti-HCV activity is effective to inhibit the function of atarget selected from HCV metalloprotease, HCV serine protease, HCVpolymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCVegress, HCV NS5A protein, IMPDH, and a nucleoside analog for thetreatment of an HCV infection.

Another aspect of the invention is a composition comprising a compound,or a pharmaceutically acceptable salt thereof, a pharmaceuticallyacceptable carrier, an interferon and ribavirin.

Another aspect of the invention is a method of inhibiting the functionof the HCV replicon comprising contacting the HCV replicon with acompound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of inhibiting the functionof the HCV NS5B protein comprising contacting the HCV NS5B protein witha compound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of treating an HCV infectionin a patient comprising administering to the patient a therapeuticallyeffective amount of a compound or a pharmaceutically acceptable saltthereof. In another embodiment the compound is effective to inhibit thefunction of the HCV replicon. In another embodiment the compound iseffective to inhibit the function of the HCV NS5B protein.

Another aspect of the invention is a method of treating an HCV infectionin a patient comprising administering to the patient a therapeuticallyeffective amount of a compound, or a pharmaceutically acceptable saltthereof, in conjunction with (prior to, after, or concurrently) anothercompound having anti-HCV activity.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is an interferon.

Another aspect of the invention is the method where the interferon isselected from interferon alpha 2B, pegylated interferon alpha, consensusinterferon, interferon alpha 2A, and lymphoblastoid interferon tau.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is a cyclosporin.

Another aspect of the invention is the method where the cyclosporin iscyclosporin A.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is selected from interleukin 2, interleukin 6,interleukin 12, a compound that enhances the development of a type 1helper T cell response, interfering RNA, anti-sense RNA, Imiqimod,ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor,amantadine, and rimantadine.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is effective to inhibit the function of atarget selected from the group consisting of HCV metalloprotease, HCVserine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCVentry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and anucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is the method where the other compoundhaving anti-HCV activity is effective to inhibit the function of targetin the HCV life cycle other than the HCV NS5B protein.

“Therapeutically effective” means the amount of agent required toprovide a meaningful patient benefit as understood by practitioners inthe field of hepatitis and HCV infection.

“Patient” means a person infected with the HCV virus and suitable fortherapy as understood by practitioners in the field of hepatitis and HCVinfection.

“Treatment,” “therapy,” “regimen,” “HCV infection,” and related termsare used as understood by practitioners in the field of hepatitis andHCV infection.

The compounds of this invention are generally given as pharmaceuticalcompositions comprised of a therapeutically effective amount of acompound or its pharmaceutically acceptable salt and a pharmaceuticallyacceptable carrier and may contain conventional excipients. Atherapeutically effective amount is that which is needed to provide ameaningful patient benefit. Pharmaceutically acceptable carriers arethose conventionally known carriers having acceptable safety profiles.Compositions encompass all common solid and liquid forms includingcapsules, tablets, losenges, and powders as well as liquid suspensions,syrups, elixers, and solutions. Compositions are made using commonformulation techniques, and conventional excipients (such as binding andwetting agents) and vehicles (such as water and alcohols) are generallyused for compositions.

Solid compositions are normally formulated in dosage units andcompositions providing from about 1 to 1000 mg of the active ingredientper dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be presentin a unit range similar to agents of that class used clinically.Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, theliquid composition will be in a unit dosage range of 1-100 mg/mL. Someexamples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100mg/mL. Generally, other agents will be present in a unit range similarto agents of that class used clinically. Typically, this is 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oraland parenteral methods are preferred. Generally, the dosing regimen willbe similar to other agents used clinically. Typically, the daily dosewill be 1-100 mg/kg body weight daily. Generally, more compound isrequired orally and less parenterally. The specific dosing regime,however, will be determined by a physician using sound medicaljudgement.

The invention also encompasses methods where the compound is given incombination therapy. That is, the compound can be used in conjunctionwith, but separately from, other agents useful in treating hepatitis andHCV infection. In these combination methods, the compound will generallybe given in a daily dose of 1-100 mg/kg body weight daily in conjunctionwith other agents. The other agents generally will be given in theamounts used therapeutically. The specific dosing regime, however, willbe determined by a physician using sound medical judgement.

Some examples of compounds suitable for compositions and methods arelisted in Table 2.

TABLE 2 Type of Inhibitor or Brand Name Target Source Company Omega IFNIFN-ω Intarcia Therapeutics BILN-2061 serine protease BoehringerIngelheim inhibitor Pharma KG, Ingelheim, Germany Summetrel antiviralEndo Pharmaceuticals Holdings Inc., Chadds Ford, PA Roferon A IFN-α2a F.Hoffmann-La Roche LTD, Basel, Switzerland Pegasys PEGylated IFN-α2a F.Hoffmann-La Roche LTD, Basel, Switzerland Pegasys and RibavirinPEGylated IFN- F. Hoffmann-La Roche α2a/ribavirin LTD, Basel,Switzerland CellCept HCV IgG F. Hoffmann-La Roche immunosuppressant LTD,Basel, Switzerland Wellferon lymphoblastoid IFN- GlaxoSmithKline plc,αn1 Uxbridge, UK Albuferon-α albumin IFN-α2b Human Genome Sciences Inc.,Rockville, MD Levovirin ribavirin ICN Pharmaceuticals, Costa Mesa, CAIDN-6556 caspase inhibitor Idun Pharmaceuticals Inc., San Diego, CAIP-501 antifibrotic Indevus Pharmaceuticals Inc., Lexington, MAActimmune INF-γ InterMune Inc., Brisbane, CA Infergen A IFN alfacon-1InterMune Pharmaceuticals Inc., Brisbane, CA ISIS 14803 antisense ISISPharmaceuticals Inc, Carlsbad, CA/Elan Phamaceuticals Inc., New York, NYJTK-003 RdRp inhibitor Japan Tobacco Inc., Tokyo, Japan Pegasys andCeplene PEGylated IFN-α2a/ Maxim Pharmaceuticals immune modulator Inc.,San Diego, CA Ceplene immune modulator Maxim Pharmaceuticals Inc., SanDiego, CA Civacir HCV IgG Nabi immunosuppressant BiopharmaceuticalsInc., Boca Raton, FL Intron A and Zadaxin IFN-α2b/α1-thymosin RegeneRxBiopharmiceuticals Inc., Bethesda, MD/ SciClone Pharmaceuticals Inc, SanMateo, CA Levovirin IMPDH inhibitor Ribapharm Inc., Costa Mesa, CAViramidine Ribavirin Prodrug Ribapharm Inc., Costa Mesa, CA Heptazymeribozyme Ribozyme Pharmaceuticals Inc., Boulder, CO Intron A IFN-α2bSchering-Plough Corporation, Kenilworth, NJ PEG-Intron PEGylated IFN-α2bSchering-Plough Corporation, Kenilworth, NJ Rebetron IFN-α2b/ribavirinSchering-Plough Corporation, Kenilworth, NJ Ribavirin ribavirinSchering-Plough Corporation, Kenilworth, NJ PEG-Intron/RibavirinPEGylated IFN- Schering-Plough α2b/ribavirin Corporation, Kenilworth, NJZadazim Immune modulator SciClone Pharmaceuticals Inc., San Mateo, CARebif IFN-β1a Serono, Geneva, Switzerland IFN-β and EMZ701 IFN-β andEMZ701 Transition Therapeutics Inc., Ontario, Canada Batabulin (T67)β-tubulin inhibitor Tularik Inc., South San Francisco, CA MerimepodibIMPDH inhibitor Vertex Pharmaceuticals (VX-497) Inc., Cambridge, MATelaprevir NS3 serine protease Vertex Pharmaceuticals (VX-950,LY-570310) inhibitor Inc., Cambridge, MA/ Eli Lilly and Co. Inc.,Indianapolis, IN Omniferon natural IFN-α Viragen Inc., Plantation, FLXTL-6865 (XTL-002) monoclonal antibody XTL Biopharmaceuticals Ltd.,Rehovot, Isreal HCV-796 NS5B Replicase Wyeth/Viropharma Inhibitor NM-283NS5B Replicase Idenix/Novartis Inhibitor GL-59728 NS5B Replicase GeneLabs/Novartis Inhibitor GL-60667 NS5B Replicase Gene Labs/NovartisInhibitor 2′C MeA NS5B Replicase Gilead Inhibitor PSI 6130 NS5BReplicase Roche Inhibitor R1626 NS5B Replicase Roche Inhibitor SCH503034 serine protease Schering Plough inhibitor NIM811 CyclophilinInhibitor Novartis Suvus Methylene blue Bioenvision Multiferon Longlasting IFN Viragen/Valentis Actilon (CPG10101) TLR9 agonist ColeyInterferon-β Interferon-β-1a Serono Zadaxin Immunomodulator SciclonePyrazolopyrimidine HCV Inhibitors Arrow Therapeutics Ltd. compounds andsalts From WO- 2005047288 26 May 2005 2′C Methyl adenosine NS5BReplicase Merck Inhibitor GS-9132 (ACH-806) HCV InhibitorAchillion/Gilead

1. A compound of formula I

where: R¹ is CO₂R⁵ or CONR⁶R⁷; R² is furanyl, pyrrolyl, thienyl,pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl,oxadiazolyl, triazolyl, or tetrazolyl, and is substituted with 0-2substituents selected from oxo, amino, alkylthio, alkyl, and haloalkyl,and 1 substituent selected from CO₂R⁵, CON(R¹²)₂, and COR¹³; R³ ishydrogen, halo, alkyl, alkenyl, hydroxy, benzyloxy, or alkoxy; R⁴ iscycloalkyl; R⁵ is hydrogen or alkyl; R⁶ is hydrogen, alkyl, alkylSO₂,cycloalkylSO₂, haloalkylSO₂, (R⁹)(R¹⁰)NSO₂, or (R¹¹)SO₂; R⁷ is hydrogenor alkyl; R⁸ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl,alkylcarbonyl, cycloalkylcarbonyl, haloalkylcarbonyl, alkoxycarbonyl,alkylSO₂, cycloalkylSO₂, haloalkylSO₂, aminocarbonyl,(alkylamino)carbonyl, (dialkylamino)carbonyl, benzyl, benzyloxycarbonyl,or pyridinyl; R⁹ is hydrogen or alkyl; R¹⁰ is hydrogen or alkyl; R¹¹ isazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl,and is substituted with 0-1 alkyl substituents; R¹² is hydrogen, alkyl,alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, or(R¹¹)alkyl; R¹³ is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, homopiperidinyl, homopiperazinyl, orhomomorpholinyl, and is substituted with 0-3 substituents selected fromalkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, R¹¹, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, (R¹¹)alkyl, or CO₂R⁵; or R¹³ is

or R¹³ is

or R¹³ is a [4.3.0] or [3.3.0] bicyclic diamine attached to the carbonylthrough one nitrogen, and is substituted with 0-2 R⁸ substituents; orR¹³ is

R¹⁴ is hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, or benzyl; R¹⁵ is hydrogen,alkyl, cycloalkyl, (cycloalkyl)alkyl, aminoalkyl, (alkylamino)alkyl,(dialkylamino)alkyl, or benzyl; or NR¹⁴R¹⁵ taken together is azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, N-(alkyl)piperazinyl,morpholinyl, thiomorpholinyl, homopiperidinyl, or homomorpholinyl; R¹⁶is hydrogen or alkyl; R¹⁷ is hydrogen, alkyl, or cycloalkyl; and X ismethylene, a bond, or absent; or a pharmaceutically acceptable saltthereof.
 2. A compound of claim 1 where: R² is furanyl, pyrrolyl,thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl,thiazolyl, oxadiazolyl, triazolyl, or tetrazolyl, and is substitutedwith 0-2 substituents selected from oxo, amino, alkyl, and haloalkyl,and 1 substituent selected from CO₂R⁵, CON(R¹²)₂, and COR¹³; and R¹³ isazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl,and is substituted with 0-3 substituents selected from alkyl,alkoxyalkyl, amino, alkylamino, dialkylamino, R¹¹, aminoalkyl,(alkylamino)alkyl, (dialkylamino)alkyl, (R¹¹)alkyl, or CO₂R⁵; or R¹³ is

or R¹³ is

or R¹³ is a [4.3.0] or [3.3.0]bicyclic diamine attached to the carbonylthrough one nitrogen, and is substituted with 0-2 R⁸ substituents; orR¹³ is

or a pharmaceutically acceptable salt thereof.
 3. A compound of claim 1where: R² is furanyl, pyrrolyl, thienyl, pyrazolyl, oxazolyl, thiazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, or tetrazolyl, and issubstituted with 0-2 substituents selected from oxo, amino, and alkyl,and 1 substituent selected from CO₂R⁵, CON(R¹²)₂, and COR¹³; R¹¹ isazetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-alkylpiperazinyl,morpholinyl, thiomorpholinyl, homopiperidinyl, homopiperazinyl, orhomomorpholinyl; and R¹³ is azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, homopiperidinyl,homopiperazinyl, or homomorpholinyl, and is substituted with 0-3substituents selected from alkyl, amino, alkylamino, dialkylamino, R¹¹,aminoalkyl, (alkylamino)alkyl, (dialkylamino)alkyl, or (R¹¹)alkyl; or apharmaceutically acceptable salt thereof.
 4. A compound of claim 1 whereR¹ is CONR⁶R⁷, R⁶ is alkylSO₂, cycloalkylSO₂, haloalkylSO₂,(R⁹)(R¹⁰)NSO₂, or (R¹¹)SO₂; and R⁷ is hydrogen.
 5. A compound of claim 1where R³ is hydrogen.
 6. A compound of claim 1 where R³ is methoxy.
 7. Acompound of claim 1 where R⁴ is cyclohexyl.
 8. A compound of claim 1where R⁶ is alkylSO₂, cycloalkylSO₂, (R⁹)(R¹⁰)NSO₂ or (R¹¹)SO₂.
 9. Acompound of claim 1 where R² is pyrazolyl substituted with 2substituents selected from alkyl and haloalkyl and 1 COR¹³ substituent;R¹³ is

R⁸ is hydrogen or alkyl; R¹⁶ is hydrogen or alkyl; and R¹⁷ is alkyl; ora pharmaceutically acceptable salt thereof.
 10. A compound of claim 1where X is methylene.
 11. A compound of claim 1 where X is absent.
 12. Acompound of claim 1 where X is a bond.
 13. A compound of claim 12 whereR¹ is CONR⁶R⁷; R² is pyrazolyl substituted with 2 substituents selectedfrom alkyl and haloalkyl and 1 COR¹³ substituent where R¹³ is

R³ is hydrogen or methoxy; R⁴ is cyclohexyl; R⁶ is alkylSO₂,cycloalkylSO₂, haloalkylSO₂, (R⁹)(R¹⁰)NSO₂, or (R¹¹)SO₂; and R⁷ ishydrogen; or a pharmaceutically acceptable salt thereof.
 14. A compoundof claim 1 selected from the group consisting of7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[2-(methoxycarbonyl)-3-thienyl]-,1,1-dimethylethyl ester; 7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid, 6-(4-carboxy-1-methyl-1H-pyrazol-5-yl)-13-cyclohexyl-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-(1,4-diazabicyclo[3.2.2]non-4-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[(1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl]carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-5-thiazolyl]-,1,1-dimethylethyl ester; 3-thiophenecarboxylic acid,2-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-(1-methylethyl)-4-[(3,4,5-trimethyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1,3-dimethyl-1H-pyrazol-5-yl]-,1,1-dimethylethyl ester; 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-;1H-pyrrole-3-carboxylic acid,2-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-(1-methylethyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-(4-morpholinylcarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[(4-methyl-1-piperazinyl)carbonyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-ethyl-3-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[2-[(diethylamino)carbonyl]-3-thienyl]-N-[(dimethylamino)sulfonyl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-5-oxazolyl]-,1,1-dimethylethyl ester; 7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid, 13-cyclohexyl-3-methoxy-6-[4-(4-morpholinylcarbonyl)-5-oxazolyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-(4-morpholinylcarbonyl)-5-oxazolyl]-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[methyl(1-methyl-3-pyrrolidinyl)amino]carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[2-[(dimethylamino)methyl]-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[(1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[[4-(1-methylethyl)-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[[4-(1-pyrrolidinyl)-1-piperidinyl]carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[3-(dimethylamino)-1-piperidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-N-[(1-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-N-[(1-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;1H-pyrrole-3-carboxylic acid,2-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-,ethyl ester; 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-(1,1-dimethylethyl)-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-[2-(4-morpholinylcarbonyl)-3-thienyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,6-[4-(7-azabicyclo[2.2.1]hept-7-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-13-cyclohexyl-3-methoxy-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[(4-methyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[3-(dimethylamino)-1-pyrrolidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,6-[4-(7-azabicyclo[2.2.1]hept-7-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-1H-pyrazol-5-yl]-;1H-pyrazole-4-carboxylic acid,5-[10-[[(cyclobutylsulfonyl)amino]carbonyl]-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-,ethyl ester; 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-6-[4-[[3-(dimethylamino)-1-piperidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-6-[4-[(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-;1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[3-(dimethylamino)-1-piperidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-3-methoxy-6-[1-methyl-4-(3-oxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1R,4R)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-(1-methylethyl)-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(3-methyl-8-azabicyclo[3.2.1]oct-2-en-8-yl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-;1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-,methyl ester; 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[4-(4-morpholinylcarbonyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-(2,2,2-trifluoroethyl)-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[3-methyl-1-(1-methylethyl)-4-[(4-methyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[3-methyl-1-(1-methylethyl)-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-ethyl-3-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[1-(1-methylethyl)-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-N-(1-pyrrolidinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[4-(4-morpholinylcarbonyl)-5-oxazolyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-N-(1-pyrrolidinylsulfonyl)-morpholine,4-[[13-cyclohexyl-6-[1-ethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-7H-indolo[2,1-a][2]benzazepin-10-yl]carbonyl]-;1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-,ethyl ester; 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-;1-piperazinecarboxylic acid,4-[[5-[13-cyclohexyl-3-methoxy-10-[[(4-morpholinylsulfonyl)amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-1H-pyrazol-4-yl]carbonyl]-,ethyl ester; 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[4-(1-pyrrolidinyl)-1-piperidinyl]carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[[(2-methoxyphenyl)methyl](1-methylethyl)amino]carbonyl]-1-methyl-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-6-[4-[[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-(3-oxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1H-pyrazol-5-yl]-N-[(1-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-(1-methylethyl)-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-;1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-,methyl ester; 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1,3-dimethyl-,methyl ester; 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1,3-dimethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-; 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[3-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-(1-methylethyl)-1H-pyrrol-2-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-(1-methylethyl)-3-(4-morpholinylcarbonyl)-1H-pyrrol-2-yl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl)carbonyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-[4-(4-morpholinylcarbonyl)-5-oxazolyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[[2-(dimethylamino)ethyl]methylamino]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(2-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-,ethyl ester; 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[[(5-ethyl-1,3,4-oxadiazol-2-yl)methyl](1-methylethyl)amino]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-N-[(1-methylpropyl)sulfonyl]-;1H-pyrazole-4-carboxylic acid,5-[10-[[(cyclobutylsulfonyl)amino]carbonyl]-13-cyclohexyl-3-methoxy-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(2-methylpropyl)sulfonyl]-6-[1-methyl-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(2,6-dimethyl-4-morpholinyl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(3-methyl-8-azabicyclo[3.2.1]oct-2-en-8-yl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[3-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1-(1-methylethyl)-1H-pyrrol-2-yl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-(1-methylethyl)-3-[(4-propyl-1-piperazinyl)carbonyl]-1H-pyrrol-2-yl]-N-[(1-methylethyl)sulfonyl]-;3-furancarboxylic acid,2-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-,ethyl ester; 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[(8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl)carbonyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-[(dimethylamino)sulfonyl]-3-methoxy-6-[1-(1-methylethyl)-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,6-(4-carboxy-5-oxazolyl)-13-cyclohexyl-3-methoxy-,10-(1,1-dimethylethyl) ester;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-ethyl-4-[(4-methyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-3-methoxy-N-(1-pyrrolidinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-ethyl-4-[(4-methyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-[4-(4-morpholinylcarbonyl)-5-oxazolyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(3-endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[(4-methyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-6-[4-[[ethyl(1-methylethyl)amino]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-(3-oxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-6-[4-[[3-(dimethylamino)-1-piperidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-[[(1-methylethyl)[(tetrahydro-2-furanyl)methyl]amino]carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[2-methypropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(methoxycarbonyl)-1,3-dimethyl-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1,3-dimethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1methylethyl)sulfonyl];7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-3-(trifluoromethyl)-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[4-(4-morpholinylcarbonyl)-5-oxazolyl]-,1,1-dimethylethyl ester; 7H-indolo[2,1-a][2]benzazepine-10-carboxylicacid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-,1,1-dimethylethyl ester; 1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[3-(dimethylamino)-1-pyrrolidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[(1-oxo-2,7-diazaspiro[4.5]dec-7-yl)carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2-methoxyethyl)(1-methylethyl)amino]carbonyl]-1-methyl-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2-methoxyethyl)(1-methylethyl)amino]carbonyl]-1-methyl-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(3-endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(dimethylamino)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[3-(dimethylamino)-1-piperidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-3-methoxy-6-[1-methyl-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-6-[4-[[(1S,4S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-6-[4-[(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-(1-methylethyl)-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[(3-methyl-3,6-diazabicyclo[3.1.1]hept-6-yl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methypropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(3-endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1methylethyl)sulfonyl];7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(3-endo)-3-hydroxy-3-methyl-8-azabicyclo[3.2.1]oct-8-yl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-;1H-pyrrole-3-carboxylic acid,2-[13-cyclohexyl-3-methoxy-10-[[[1-methylethyl)sulfonyl]amino]carbonyl]-7H-indolo[21-a][2]benzazepin-6-yl]-1-(1-methylethyl)-,ethyl ester; 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[4-(3-oxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-[1,3-dimethyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1-(1,1-dimethylethyl)-4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylcarbonyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylcarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[3-methyl-1-(1-methylethyl)-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[4-(1-methylethyl)-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[3-(dimethylamino)-1-piperidinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[2-(1-piperidinylmethyl)-1-pyrrolidinyl]carbonyl]-1H-pyrazol-5-yl]-N-(4-morpholinylsulfonyl)-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,6-[4-[[[2-[bis(1-methylethyl)amino]ethyl](1-methylethyl)amino]carbonyl]-1-methyl-1H-pyrazol-5-yl]-13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-(cyclopentylsulfonyl)-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylpropyl)sulfonyl]-6-[1-methyl-4-[(3,4,5-trimethyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-;1H-pyrazole-4-carboxylic acid,5-[13-cyclohexyl-3-methoxy-10-[[[(1-methylpropyl)sulfonyl]amino]carbonyl]-7H-indolo[2,1-a][2]benzazepin-6-yl]-1-methyl-,ethyl ester; 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[1-methyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-N-[(2-methylpropyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-3-methoxy-6-[1-methyl-4-[[(3R,5S)-3,4,5-trimethyl-1-piperazinyl]carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-3-methoxy-6-[1-methyl-4-(3-oxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-6-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-ylcarbonyl)-1-methyl-1H-pyrazol-5-yl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,N-(cyclobutylsulfonyl)-13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-methyl-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[3-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-2-thienyl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[4-(ethoxycarbonyl)-2-(methylthio)-5-thiazolyl]-3-methoxy-,1,1-dimethylethyl ester; 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(1S)-5-ethyl-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-[1,3-dimethyl-4-(4-morpholinylcarbonyl)-1H-pyrazol-5-yl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[1,3-dimethyl-4-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[1-(1,1-dimethylethyl)-4-(ethoxycarbonyl)-1H-pyrazol-5-yl]-3-methoxy-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[3-[(3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl)carbonyl]-2-furanyl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[3-(4-morpholinylcarbonyl)-2-furanyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-(2-methylpropyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid,13-cyclohexyl-6-[1-ethyl-4-(methoxycarbonyl)-3-methyl-1H-pyrazol-5-yl]-3-methoxy-;5H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[3-[(dimethylamino)carbonyl]-5-methyl-4H-1,2,4-triazol-4-yl]-N-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-;and 5H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[3-[(dimethylamino)carbonyl]-4H-1,2,4-triazol-4-yl]-N-[(dimethylamino)sulfonyl]-6,7-dihydro-3-methoxy-;or a pharmaceutically acceptable salt thereof.
 15. A compositioncomprising a compound of claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 16. A method oftreating hepatitis C infection comprising administering atherapeutically effective amount of a compound of claim 1 to a patient.17. A compound of claim 1 selected from the group consisting of7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[(2,6-dimethyl-4-morpholinyl)carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-(1-methylethyl)-4-[(3,4,5-trimethyl-1-piperazinyl)carbonyl]-1H-pyrazol-5-yl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-6-[4-[[(2S)-2-(methoxymethyl)-4-morpholinyl]carbonyl]-1-(1-methylethyl)-1H-pyrazol-5-yl]-N-[(1-methylethyl)sulfonyl]-;7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-6-[4-[[(2R,6S)-2,6-dimethyl-4-morpholinyl]carbonyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]-3-methoxy-N-[(1-methylethyl)sulfonyl]-;and 7H-indolo[2,1-a][2]benzazepine-10-carboxamide,13-cyclohexyl-3-methoxy-N-[(1-methylethyl)sulfonyl]-6-[1-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-ylcarbonyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-;or a pharmaceutically acceptable salt thereof.